To Örebro University

oru.seÖrebro University Publications
Change search
Refine search result
123 1 - 50 of 115
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Adolfsson, Emma
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Porath, Sandra
    Örebro University Hospital, Örebro, Sweden.
    Andershed, Anna Nowosad
    Örebro University Hospital, Örebro, Sweden.
    External validation of a time-lapse model: a retrospective study comparing embryo evaluation using a morphokinetic model to standard morphology with live birth as endpoint2018In: Jornal Brasileiro de Reproducao Assistida, ISSN 1517-5693, Vol. 22, no 3, p. 205-214Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To validate a morphokinetic implantation model developed for EmbryoScope on embryos with known outcome, compared to standard morphology in a retrospective single center study.

    METHODS: Morphokinetic annotation of 768 embryos with known outcome between 2013 -2015; corresponding to 116 D3 fresh embryos, 80 D6 frozen blastocysts, and 572 D5 blastocysts, fresh or frozen. The embryos were ranked by the KIDScore into five classes, KID1-5, and grouped into four classes based on standard morphology. Pregnancy rates, clinical pregnancy rates and live birth rates were compared. Combinations of morphology and morphokinetics were evaluated for implantation rates and live births.

    RESULTS: Live birth rate increased with increasing KIDScore, from 19% for KID1 to 42% for KID5. Of all live births, KID5 contributed with 71%, KID4 with 20%, KID3 with 4%, KID2 with 4%, and KID1 with 2%. For morphology, the corresponding figure was 43% for Top Quality, 47% for Good Quality, 4% for Poor Quality, and 5% for Slow embryos. For day 3 embryos, KID5 embryos had the highest live birth rates, and contributed to 83% of the live births; whereas the second best morphological class had the highest live birth rate and contributed to most of the live births. For blastocysts, the KIDScore and morphology performed equally well. Combining morphology and morphokinetics indicated stronger predictive power for morphokinetics.

    CONCLUSIONS: Overall, the KIDScore correlates with both implantation and live birth in our clinical setting. Compared to morphology, the KIDScore was superior for day 3 embryos, and equally good for blastocysts at predicting live births.

  • 2.
    Alanay, Yasemin
    et al.
    Pediatric Genetics, Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Kayisdagi Cad. No:32, Atasehir, 34684, Istanbul, Turkey.
    Mohnike, Klaus
    Department of Pediatrics, Otto-von-Guericke-University, Magdeburg, Germany.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Department of Medical Sciences, Örebro University, Örebro, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Alves, Inês
    ANDO Portugal, Évora, Portugal.
    AlSayed, Moeenaldeen
    Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
    Appelman-Dijkstra, Natasha M.
    Department of Internal Medicine, Division Endocrinology and Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands.
    Baujat, Genevieve
    Hôpital Necker Enfants Malades AP-HP, Paris, France.
    Ben-Omran, Tawfeg
    Genetic and Genomic Medicine Division, Sidra Medicine and Hamad Medical Corporation, Doha, Qatar.
    Breyer, Sandra
    Department of Paediatrics, UKE Hamburg-Eppendorf, Hamburg, Germany.
    Cormier-Daire, Valerie
    Hôpital Necker Enfants Malades AP-HP, Paris, France; Reference Center for Skeletal Dysplasia, Imagine Institute, Paris Cité University, Paris, France.
    Gregersen, Pernille Axél
    Department of Clinical Genetics and Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
    Guillén-Navarro, Encarna
    Medical Genetics Section, Department of Paediatrics, Virgen de la Arrixaca University Clinical Hospital, IMIB-Arrixaca, Faculty of Medicine, University of Murcia (UMU), Murcia, Spain.
    Högler, Wolfgang
    Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria.
    Maghnie, Mohamad
    Department of Paediatrics, IRCCS Istituto Giannna Gaslini, Genoa, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology Genetics, Maternal and Child-Health, University of Genova, Genoa, Italy.
    Mukherjee, Swati
    BioMarin (UK) Limited, London, UK.
    Cohen, Shelda
    BioMarin (UK) Limited, London, UK.
    Pimenta, Jeanne
    BioMarin (UK) Limited, London, UK.
    Selicorni, Angelo
    Pediatric Unit ASST Lariana, Mariani Center for Fragile Child, Como, Italy.
    Semler, J. Oliver
    Faculty of Medicine, University of Cologne, Cologne, Germany; Department of Pediatrics, University Hospital Cologne, Cologne, Germany.
    Sigaudy, Sabine
    Département de Génétique Médicale, Hôpital Timone Enfant, Marseille, France.
    Popkov, Dmitry
    National Ilizarov Research Center for Traumatology and Orthopaedics, Kurgan, Russia.
    Sabir, Ian
    BioMarin (UK) Limited, London, UK.
    Noval, Susana
    Fundación ALPE Acondroplasia, Asturias, Spain.
    Sessa, Marco
    Associazione per I'Informazione e lo Studio dell'Acondroplasia (AISAC), Milan, Italy.
    Irving, Melita
    Guy's and St. Thomas' NHS Foundation Trust, Evelina Children's Hospital, London, UK.
    Real-world evidence in achondroplasia: considerations for a standardized data set2023In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 18, no 1, article id 166Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes.

    METHODS: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes.

    RESULTS: A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments.

    CONCLUSIONS: Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.

  • 3.
    Alexandraki, Krystallenia I.
    et al.
    Second Department of Surgery, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece.
    Spyroglou, Ariadni
    Second Department of Surgery, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece; Clinic for Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.
    Kykalos, Stylianos
    Second Department of Propaedeutic Surgery, Laiko Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
    Daskalakis, Kosmas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Endocrine Unit, First Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Kyriakopoulos, Georgios
    Department of Pathology, Evaggelismos Hospital, Athens, Greece.
    Sotiropoulos, Georgios C.
    Clinic for Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.
    Kaltsas, Gregory A.
    Endocrine Unit, First Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Grossman, Ashley B.
    Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK; NET Unit, Royal Free Hospital, London, UK; Barts and the London School of Medicine, London, UK.
    Changing biological behaviour of NETs during the evolution of the disease: progress on progression2021In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 28, no 5, p. R121-R140, article id ERC-20-0473Article, review/survey (Refereed)
    Abstract [en]

    Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.

  • 4. Ali, Magdi M. M.
    et al.
    ElGhazali, Gehad
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Farouk, Salah E.
    Nasr, Amre
    Noori, Suzan I. A.
    Shamad, Mahdi M.
    Fadlelseed, Omar E.
    Berzins, Klavs
    Fc gamma RIIa (CD32) polymorphism and onchocercal skin disease: implications for the development of severe reactive onchodermatitis (ROD)2007In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 77, no 6, p. 1074-8Article in journal (Refereed)
    Abstract [en]

    The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the Fc gamma RIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. Fc gamma RIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). Fc gamma RIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

  • 5.
    Ariceta, Gema
    et al.
    Department of Pediatric Nephrology, Hospital Vall d'Hebron, Universitat Autonoma Barcelona, Barcelona, Spain.
    Beck-Nielsen, Signe Sparre
    Centre for Rare Diseases, Aarhus University Hospital, Åarhus, Denmark; Department of Clinical Medicine, Aarhus University, Åarhus, Denmark.
    Boot, Annemieke M.
    Department of Pediatrics, Division of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
    Brandi, Maria Luisa
    FIRMO Foundation, Florence, Italy; Donatello Bone Clinic, Florence, Italy.
    Briot, Karine
    Hôpital Cochin, Service de Rhumatologie, Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphate Filière OSCAR, AP-HP, Paris, France.
    de Lucas Collantes, Carmen
    Universidad Autónoma de Madrid, Madrid, Spain; Hospital Infantili Niño Jesús, Madrid, Spain.
    Emma, Francesco
    Division of Nephrology, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy.
    Giannini, Sandro
    Department of Medicine, Clinica Medica 1, University of Padova, Padua, Italy.
    Haffner, Dieter
    Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
    Keen, Richard
    Royal National Orthopaedic Hospital, Stanmore, UK.
    Levtchenko, Elena
    Department of Pediatric Nephrology and Development and Regeneration, University Hospitals Leuven, University of Leuven, Leuven, Belgium.
    Mӓkitie, Outi
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Mughal, M. Zulf
    Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester University Hospital's NHS Trust, Manchester, UK.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; School of Medical Sciences and Department of Pediatrics, University Hospital, Örebro, Sweden.
    Schnabel, Dirk
    Center for Chronically Sick Children, Pediatric Endocrinology, Charité, University Medicine Berlin, Berlin, Germany.
    Tripto-Shkolnik, Liana
    Division of Endocrinology, Diabetes and Metabolism, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
    Liu, Jonathan
    Kyowa Kirin International, Marlow, UK.
    Williams, Angela
    Kyowa Kirin International, Marlow, UK.
    Wood, Sue
    Kyowa Kirin International, Marlow, UK.
    Zillikens, M. Carola
    Bone Center, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
    The International X-Linked Hypophosphatemia (XLH) Registry: first interim analysis of baseline demographic, genetic and clinical data2023In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 18, no 1, article id 304Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient's lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry.

    RESULTS: The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately - 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH.

    CONCLUSION: The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.

  • 6.
    Assadi, G.
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Saleh, R.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Hadizadeh, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Vesterlund, L.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bonfiglio, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Törkvist, L.
    Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, A. S.
    Gatroenterology Unit, Department of Internal Medicine, Sahlgren's University Hospital/Östra, Göteborg, Sweden.
    Harris, H. E.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sundberg, E.
    Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, M.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
    LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis2016In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 17, no 4, p. 261-264Article in journal (Refereed)
    Abstract [en]

    The function of the Laccase domain-containing 1 (LACC1) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1's link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).

  • 7.
    Beaudoin, Melissa
    et al.
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Goyette, Philippe
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Boucher, Gabrielle
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Lo, Ken Sin
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Rivas, Manuel A.
    Center for the Study of IBD (CSIBD) Genetics, The Broad Institute, Cambridge MA, United States.
    Stevens, Christine
    Center for the Study of IBD (CSIBD) Genetics, The Broad Institute, Cambridge MA, United States.
    Alikashani, Azadeh
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Ladouceur, Martin
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Ellinghaus, David
    Christian-Albrechts-University, Kiel, Germany.
    Törkvist, Leif
    Karolinska Institutet, Stockholm, Sweden.
    Goel, Gautam
    Harvard School of Medicine, Boston MA, USA.
    Lagace, Caroline
    Research Center, Montreal Heart Institute, Montreal QC, Canada.
    Annese, Vito
    Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Unit of Gastroenterology SOD2, Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy.
    Bitton, Alain
    McGill University Health Centre, Royal Victoria Hospital, Montreal QC, Canada.
    Begun, Jakob
    Harvard School of Medicine, Boston MA, USA.
    Brant, Steve R.
    Johns Hopkins University, Baltimore MD, USA.
    Bresso, Francesca
    Karolinska University Hospital, Solna, Sweden.
    Cho, Judy H.
    Yale University, New Haven CT, USA.
    Duerr, Richard H.
    Graduate School of Public Health, University of Pittsburgh, Pittsburgh PA, USA.
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    McGovern, Dermot P. B.
    Cedars-Sinai Medical Center, Los Angeles CA, USA.
    Radford-Smith, Graham
    University of Queensland, Brisbane, Australia.
    Schreiber, Stefan
    Christian-Albrechts-University, Kiel, Germany.
    Schumm, Philip L.
    University of Chicago, Chicago ILL, USA.
    Sharma, Yashoda
    Yale University, New Haven CT, USA.
    Silverberg, Mark S.
    University of Toronto, Toronto ON, Canada.
    Weersma, Rinse K.
    University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
    D'Amato, Mauro
    Karolinska Institutet, Stockholm, Sweden.
    Vermeire, Severine
    University Hospital Gasthuisberg, Leuven, Belgium.
    Franke, Andre
    Christian-Albrechts-University, Kiel, Germany.
    Lettre, Guillaume
    Research Center, Montreal Heart Institute, Montreal QC, Canada; Universite de Montreal, Montreal QC, Canada .
    Xavier, Ramnik J.
    Harvard School of Medicine, Boston MA, USA; Broad Institute of MIT and Harvard University, Cambridge MA, USA .
    Daly, Mark J.
    Massachusetts General Hospital, Harvard Medical School, Boston MA, USA.
    Rioux, John D.
    Research Center, Montreal Heart Institute, Montreal QC, Canada; Universite de Montreal, Montreal QC, Canada.
    Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 9, article id e1003723Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (similar to 14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

  • 8.
    Beck-Nielsen, Signe Sparre
    et al.
    Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
    Mughal, Zulf
    Royal Manchester Children's Hospital, Manchester, UK.
    Haffner, Dieter
    Hannover Medical School, Hannover, Germany.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden .
    Levtchenko, Elena
    Katholieke Universiteit Leuven, Leuven, Belgium.
    Ariceta, Gema
    Hospital Universitario Materno-Infantil Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
    de Lucas Collantes, Carmen
    Hospital Niño Jesús, Madrid, Spain.
    Schnabel, Dirk
    University Children's Hospital of Berlin, Berlin, Germany.
    Jandhyala, Ravi
    Medialis Ltd, Banbury, UK.
    Mäkitie, Outi
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    FGF23 and its role in X-linked hypophosphatemia-related morbidity2019In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 14, no 1, article id 58Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood.

    METHODS: The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH.

    RESULTS: The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations.

    CONCLUSIONS: By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.

  • 9.
    Bento, Celeste
    et al.
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    Percy, Melanie J.
    Department of Haematology, Belfast City Hospital, Belfast, United Kingdom .
    Gardie, Betty
    Unité Mixte de Recherche (UMR) 892 Inserm - 6299 CNRS, Université de Nantes, Nantes, France; Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), INSERM U753, Institut de cancérologie Gustave Roussy, Villejuif, France .
    Maia, Tabita Magalhaes
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    van Wijk, Richard
    Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, Netherlands .
    Perrotta, Silverio
    Dipartimento della Donna, Del Bambino e di Chirurgia Generale e Specialistica, Second University of Naples, Naples, Italy .
    Della Ragione, Fulvio
    Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy .
    Almeida, Helena
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    Rossi, Cedric
    Laboratoire d'Hématologie, Centre Hospitalier Universitaire Dijon, Dijon, France .
    Girodon, Francois
    Laboratoire d'Hématologie, Centre Hospitalier Universitaire Dijon, Dijon, France .
    Åström, Maria
    Örebro University Hospital. Departments of Medicine and Laboratory Medicine.
    Neumann, Drorit
    Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel .
    Schnittger, Susanne
    Munich Leukemia Laboratory (MLL), Munich, Germany .
    Landin, Britta
    Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden .
    Minkov, Milen
    Department of Hematology/Oncology, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria .
    Randi, Maria Luigia
    Department of Medicine DIMED, University of Padua, Padua, Italy .
    Richard, Stephane
    Laboratoire de Génétique Oncologique de l'Ecole Pratique des Hautes Etudes (EPHE), INSERM U753, Institut de cancérologie Gustave Roussy, Villejuif, France .
    Casadevall, Nicole
    Hôpital Saint Antoine, Paris, France; Assistance Publique-Hôpitaux de Paris, Paris, France; Pierre et Marie Curie University, Paris, France; UMR1009 Institut Gustave Roussy Villejuif, Paris, France .
    Vainchenker, William
    UMR 1009 and GRex, INSERM, Université Paris-Sud, Institut Gustave Roussy, Villejuif, France .
    Rives, Susana
    Department of Pediatric Hematology, Hospital Sant Joan de Déu de Barcelona, University of Barcelona, Barcelona, Spain .
    Hermouet, Sylvie
    Unité Mixte de Recherche (UMR) 892 Inserm - 6299 CNRS, Université de Nantes, Nantes, France .
    Ribeiro, M. Leticia
    Department of Hematology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal .
    McMullin, Mary Frances
    Department of Haematology, CCRCB, Queen's University, Belfast, Northern Ireland, United Kingdom .
    Cario, Holger
    Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany .
    Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases2014In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 35, no 1, p. 15-26Article in journal (Refereed)
    Abstract [en]

    Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.

  • 10.
    Bereketoglu, Ceyhun
    et al.
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Andersson, Patrik L.
    Department of Chemistry, Umeå University, Umeå, Sweden.
    Stasinopoulou, Sotiria
    Molecular Endocrinology Program, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Mitsiou, Dimitra J.
    Molecular Endocrinology Program, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Alexis, Michael N.
    Molecular Endocrinology Program, Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    The brominated flame retardants TBECH and DPTE alter prostate growth, histology and gene expression patterns in the mouse2021In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 102, p. 43-55Article in journal (Refereed)
    Abstract [en]

    The brominated flame retardants (BFRs), 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) bind to the androgen receptor (AR). In vitro bioassays have shown that TBECH is a potent androgen agonist while DPTE is a potent AR antagonist. Both TBECH and DPTE alter gene expression associated with AR regulation. However, it remains to be determined if TBECH and DPTE can affect the prostate. For this reason, we exposed CD1 mice to a 1:1 mixture of TBECH diastereomers α and β, a 1:1 mixture of γ and δ, and to DPTE, and tested their effects on prostate growth, histology and gene expression profiles. Castrated (C) mice were used to study the androgenic effects of TBECHαβ and TBECHγδ while the antagonistic effects of DPTE were studied in non-castrated (NC) mice. We observed that testosterone and TBECHγδ increased body and prostate weights while TBECHαβ affected neither of them; and that DPTE had no effect on body weight but reduced prostate weight drastically. Histomorphometric analysis of the prostate revealed epithelial and glandular alterations in the TBECHγδ group comparable to those in testosterone group while alterations in the TBECHαβ group were less pronounced. DPTE displayed androgen antagonist activity reminiscent of castration. The transcription profile of the prostate was altered by castration and exposure to testosterone and to TBECHγδ reversed several of these changes. Testosterone and TBECHγδ also regulated the expression of several androgen responsive genes implicated in prostate growth and cancer. While DPTE resulted in a drastic reduction in prostate weight, it only affected a small number of genes. The results indicate that TBECHγδ and DPTE are of high human health concern as they may contribute to changes in prostate growth, histology and function.

  • 11.
    Berg von Linde, Maria
    et al.
    Department of Cardiology, Faculty of Health, Örebro University, Örebro, Sweden.
    Johansson, Karin
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Center, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Samano, Ninos
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery.
    Friberg, Örjan
    Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Frøbert, Anne Mette
    Department of Chemistry and Bioscience, Faculty of Engineering and Science, Aalborg University, Aalborg, Denmar.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Expression of Paracrine Effectors in Human Adipose-Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos)2021In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 14, no 1, p. 317-325Article in journal (Refereed)
    Abstract [en]

    Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for novel cell therapeutic applications. Hibernating brown bears sustain tissue integrity and function via unknown mechanisms, which might be plasma borne. We hypothesized that plasma from hibernating bears may increase the expression of favorable factors from human ADSCs. In an experimental study, ADSCs from patients with ischemic heart disease were treated with interventional media containing plasma from hibernating and active bears, respectively, and with control medium. Extracted RNA from the ADSCs was sequenced using next generation sequencing. Statistical analyses of differentially expressed genes were performed using fold change analysis, pathway analysis, and gene ontology. As a result, we found that genes associated with inflammation, such as IGF1, PGF, IL11, and TGFA, were downregulated by > 10-fold in ADSCs treated with winter plasma compared with control. Genes important for cardiovascular development, ADM, ANGPTL4, and APOL3, were upregulated in ADSCs when treated with winter plasma compared with summer plasma. ADSCs treated with bear plasma, regardless if it was from hibernating or active bears, showed downregulation of IGF1, PGF, IL11, INHBA, IER3, and HMOX1 compared with control, suggesting reduced cell growth and differentiation. This can be summarized in the conclusion that plasma from hibernating bears suppresses inflammatory genes and activates genes associated with cardiovascular development in human ADSCs. Identifying the involved regulator(s) holds therapeutic potential.

  • 12.
    Bladen, Catherine L.
    et al.
    Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Medical Research Council, Newcastle Upon Tyne, England.
    Rafferty, Karen
    Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Medical Research Council, Newcastle Upon Tyne, England.
    Straub, Volker
    Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Medical Research Council, Newcastle Upon Tyne, England.
    Monges, Soledad
    Moresco, Angelica
    Hosp Pediat JP Garrahan, Buenos Aires DF, Argentina..
    Dawkins, Hugh
    Department of Health, Office of Population Health Genomics, Perth WA, Australia.
    Roy, Anna
    The Scientific Institute of Public Health (WIV ISP), Brussels, Belgium.
    Chamova, Teodora
    Dept Neurol, Sofia, Med Univ Sofia, Sofia, Bulgaria.
    Guergueltcheva, Velina
    Dept Neurol, Med Univ Sofia, Sofia, Bulgaria.
    Korngut, Lawrence
    Hlth Sci Ctr, Univ Calgary, Calgary AB, Canada.
    Campbell, Craig
    Dept Paediat Clin Neurol Sci & Epidemiol, Univ Western Ontario, London ON, Canada.
    Dai, Yi
    Dept Neurol, Peking Union Med Coll Hosp, Peking Union Med Coll, Beijing , Peoples R China; Chinese Acad Med Sci, Beijing, Peoples R China.
    Barisic, Nina
    Sch Med, Div Paediat Neurol, Univ Hosp Ctr, Univ Zagreb, Zagreb, Croatia.
    Kos, Tea
    Sch Med, Div Paediat Neurol, Univ Hosp Ctr, Univ Zagreb, Zagreb, Croatia.
    Brabec, Petr
    Inst Biostat & Anal, Masaryk Univ, Brno, Czech Republic..
    Rahbek, Jes
    Natl Danish Rehabil Ctr Neuromuscular Dis, Aarhus, Denmark.
    Lahdetie, Jaana
    Cent Hosp, Turku Univ, Turku, Finland.
    Tuffery-Giraud, Sylvie
    Lab Genet Malad Rares, Univ Montpellier I, Montpellier, France; INSERM, Montpellier, France.
    Claustres, Mireille
    Lab Genet Malad Rares, Univ Montpellier I, Montpellier, France; INSERM, Montpellier, France.
    Leturcq, France
    Lab Biochim & Genet Mol, Hop Cochin, Paris, France..
    Ben Yaou, Rabah
    Lab Biochim & Genet Mol, Hop Cochin, Paris, France.
    Walter, Maggie C.
    Dept Neurol, Friedrich Baur Inst, Univ Munich, Munich, Germany.
    Schreiber, Olivia
    Dept Neurol, Friedrich Baur Inst, Univ Munich, Munich, Germany.
    Karcagi, Veronika
    Dept Mol Genet, National Institute of Environmental Health, Budapest, Hungary.
    Herczegfalvi, Agnes
    Dept Mol Genet, National Institute of Environmental Health, Budapest, Hungary.
    Viswanathan, Venkatarman
    Kanchi Kamakoti CHILDS Trust Hosp, Madras, India.
    Bayat, Farhad
    Pasteur Inst Iran, Tehran, Iran.
    Sarmiento, Isis de la Caridad Guerrero
    Pasteur Inst Iran, Tehran, Iran.
    Ambrosini, Anna
    Foundation Telethon Piazza Cavour, Milan, Italy.
    Ceradini, Francesca
    Hosp Pediat JP Garrahan, Buenos Aires DF, Argentina; Parent Project Onlus, Rome, Italy.
    Kimura, En
    Translat Med Ctr, Natl Ctr Neurol & Psychiat Kodaira, Tokyo, Japan.
    van den Bergen, Janneke C.
    Med Ctr, Dept Neurol, Leiden Univ, Leiden, Netherlands.
    Rodrigues, Miriam
    Auckland City Hosp, Auckland, New Zealand.
    Roxburgh, Richard
    Auckland City Hosp, Auckland, New Zealand..
    Lusakowska, Anna
    Warszawa Banacha 1A, Dept Neurol, Warsaw, Poland.
    Oliveira, Jorge
    Ctr Genet Med Jacinto Magalhaes, Oporto, Portugal..
    Santos, Rosario
    Ctr Genet Med Jacinto Magalhaes, Oporto, Portugal..
    Neagu, Elena
    Pediat Neurol Dept, Hosp Al Obregia, Bucharest, Romania..
    Butoianu, Niculina
    Pediat Neurol Dept, Hosp Al Obregia, Bucharest, Romania..
    Artemieva, Svetlana
    Rublevskoe Shosse, Moscow, Russia..
    Rasic, Vedrana Milic
    Clin Child Neurol & Psychiat, Belgrade, Serbia..
    Posada, Manuel
    Inst Rare Dis Res, Inst Hlth Carlos III, Madrid, Spain.
    Palau, Francesc
    Unit Genet, Hosp La Fe, Valencia, Spain..
    Lindvall, Björn
    Örebro University Hospital.
    Bloetzer, Clemens
    Paediat Neurol & Neurorehabil Unit, Univ Lausanne Hosp, Lausanne, Switzerland..
    Karaduman, Ayse
    Fac Hlth Sci, Dept Physiotherapy & Rehabil, Hacettepe Univ, Ankara, Turkey..
    Topaloglu, Haluk
    Fac Hlth Sci, Dept Physiotherapy & Rehabil, Hacettepe Univ, Ankara, Turkey..
    Inal, Serap
    Dept Neurol, PTR Unit, Istanbul Univ, Fac Med, Istanbul, Turkey..
    Oflazer, Piraye
    Dept Neurol, PTR Unit, Istanbul Univ, Fac Med, Istanbul, Turkey..
    Stringer, Angela
    Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle upon Tyne, United Kingdom; Division of Paediatric Neurology, University Hospital Centre Zagreb (KBC Zagreb), University of Zagreb Medical School, Zagreb, Croatia; Act Duchenne, Epictr, London, England..
    Shatillo, Andriy V.
    Inst Neurol Psychiat & Narcol NAMS, Kharkov, Ukraine..
    Martin, Ann S.
    DuchenneConnect, Hackensack NJ, USA.
    Peay, Holly
    DuchenneConnect, Hackensack NJ, USA.
    Flanigan, Kevin M.
    Ohio State Univ, Columbus OH, USA.;Nationwide Childrens Hosp, Columbus OH, USA.
    Salgado, David
    Fac Med Timone INSERM, UMR S910, Aix Marseille Univ, Marseille, France; Australian Regenerat Med Inst, EMBL Australia, Monash Univ, Clayton Vic, Australia.
    von Rekowski, Brigitta
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Lynn, Stephen
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Heslop, Emma
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Gainotti, Sabina
    Annali dell'Istituto Superiore di Sanità, Natl Ctr Rare Dis, Rome, Italy.
    Taruscio, Domenica
    Annali dell'Istituto Superiore di Sanità, Natl Ctr Rare Dis, Rome, Italy.
    Kirschner, Jan
    Univ Med Ctr, Freiburg, Germany..
    Verschuuren, Jan
    Dept Neurol, ZA, Leiden Univ, Med Ctr, Leiden, Netherlands.
    Bushby, Kate
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne, England..
    Beroud, Christophe
    Fac Med Timone, INSERM, UMR S910, Aix Marseille Univ, Marseille, France..
    Lochmueller, Hanns
    MRC, Ctr Neuromuscular Dis Newcastle, Inst Med Genet, Newcastle Upon Tyne , England..
    The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 11, p. 1449-1457Article in journal (Refereed)
    Abstract [en]

    Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence<5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

  • 13.
    Bogl, Leonie H.
    et al.
    Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, Los Angeles CA, United States.
    Kaprio, Jaakko
    Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
    Does the sex of one's co-twin affect height and BMI in adulthood?: A study of dizygotic adult twins from 31 cohorts2017In: Biology of Sex Differences, ISSN 2042-6410, Vol. 8, no 1, article id 14Article in journal (Refereed)
    Abstract [en]

    Background: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs.

    Methods: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese.

    Results: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance.

    Conclusions: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.

  • 14.
    Bruder, Carl E. G.
    et al.
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Hirvelä, Carina
    Department of Otorhinolaryngology and Head and Neck Surgery, Uppsala University Hospital, Uppsala, Sweden.
    Tapia-Paez, Isabel
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Fransson, Ingegerd
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Segraves, Richard
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Hamilton, Greg
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Zhang, Xiao Xiao
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Evans, D. Gareth
    Department of Medical Genetics, St Mary Hospital, Manchester, UK.
    Wallace, Andrew J.
    Department of Medical Genetics, St Mary Hospital, Manchester, UK.
    Baser, Michael E.
    Los Angeles, USA.
    Zucman-Rossi, Jessica
    Laboratorie de Geneticque des Tumeurs, Paris, France.
    Hergersberg, Martin
    Institute of Medical Genetics, University of Zürich, Zürich, Switzerland.
    Boltshauser, Eugene
    Division of Pediatric Neurology, Children Hospital, Zürich, Switzerland .
    Papi, Laura
    Medical Genetics Unit, Department of Physiopathology, University of Florence, Florence, Italy.
    Rouleau, Guy A.
    Centre for Research in Neuroscience, Montreal General Hospital, Quebec, Canada.
    Poptodorov, George
    Department of Neurosurgery, University Hospital, Sofia, Bulgaria.
    Jordanova, Albena
    Laboratory of Molecular Pathology, Sofia, Bulgaria.
    Rask-Andersen, Helge
    Department of Otorhinolaryngology and Head and Neck Surgery, Uppsala University Hospital, Uppsala, Sweden.
    Kluwe, Lan
    Department of Neurology, Klinikum Nord Ochenzoll, Hamburg, Germany.
    Mautner, Victor
    Department of Neurology, Klinikum Nord Ochenzoll, Hamburg, Germany.
    Sainio, Markku
    Department of Pathology, University of Helsinki, Haartman Institute, Helsinki, Finland.
    Hung, Gene
    House Ear Institute, Los Angeles, USA.
    Mathiesen, Tiit
    Department of Neurosurgery, Karolinska Hospital, Stockholm, Sweden.
    Möller, Claes
    Department of Audiology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Pulst, Stefan M.
    Division of Neurology, Cedars-Sinai Medical Center, Los Angeles USA.
    Harder, Henrik
    Department of Otorhinolaryngology, Linköping University Hospital, Linköping, Sweden.
    Heiberg, Arvid
    Department of Medical Genetics, Rikshospitalet, Oslo, Norway.
    Honda, Mariko
    Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.
    Niimura, Michihito
    Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.
    Sahlén, Sigrid
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Blennow, Elisabeth
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Albertson, Donna G.
    Cancer Research Institute, UCSF Cancer Center, San Francisco, USA.
    Pinkel, David
    Department of Laboratory Medicine, UCSF Cancer Center, San Fancisco, USA.
    Dumanski, Jan P.
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden; Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University Hospital, Uppsala, Sweden.
    High resolution deletion analysis of conctitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH2001In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 10, no 3, p. 271-282Article in journal (Refereed)
    Abstract [en]

    Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CON methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.

  • 15.
    Busi, Micol
    et al.
    Audiology Department, University of Ferrara, Ferrara, Italy.
    Castiglione, Alessandro
    Audiology Department, University of Ferrara, Ferrara, Italy.
    Taddei Masieri, Marina
    Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Ferrara, Italy.
    Ravani, Anna
    Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Ferrara, Italy.
    Guaran, Valeria
    Biomedical Campus, Padua University, Padua, Italy.
    Astofi, Laura
    Biomedical Campus, Padua University, Padua, Italy.
    Trevisi, Patrizia
    Audiology Department, University of Ferrara, Ferrara, Italy.
    Ferlini, Alessandra
    Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Ferrara, Italy.
    Martini, Alessandro
    ENT – Otosurgery Department, Padua University, Padua, Italy.
    Novel mutations in the SLC26A4 gene2012In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 76, no 9, p. 1249-1254Article in journal (Refereed)
    Abstract [en]

    Objectives: Mutations in the SLC26A4 gene (7q22.3–7q31.1) are considered one of the most common causes of genetic hearing loss. There are two clinical forms related to these mutations: syndromic and non-syndromic deafness. The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present. Both are transmitted as an autosomal recessive trait, but simple heterozygotes can develop both forms of deafness. Actually it is thought that Pendred Syndrome occurs when both alleles of SLC26A4 gene are mutated; DFNB4 seems due to monoallelic mutations. PS and DFNB4 can be associated with inner ear malformations. In most of the cases (around 80%), these consist in Enlarged Vestibular Aqueduct (EVA). EVA can also be present without SLC26A4 mutations.

    Understanding the role of new SLC26A4 variants should facilitate clinical assessment, as well as diagnostic and therapeutic approaches. This investigation aims to detect and report genetic causes of two unrelated Italian boys with hearing loss.

    Methods: Patients and family members underwent clinical, audiological and genetic evaluations. To identify genetic mutations, DNA sequencing of SLC26A4 gene (including all 21 exons, exon-intron boundaries and promoter region) was carried out.

    Results: Both probands were affected by congenital, progressive and fluctuating mixed hearing loss. Temporal bone imaging revealed a bilateral EVA with no other abnormalities in both cases. Probands were heterozygotes for previously undescribed mutations in the SLC26A4 gene: R409H/IVS2+1delG (proband 1) and L236P/K590X (proband 2). No other mutations were detected in GJB2, GJB6 genes or mitochondrial DNA (mit-DNA).

    Conclusions: The IVS2+1delG and K590X mutations have not yet been described in literature but there is some evidence to suggest that they have a pathological role. The results underlined the importance of considering the complete DNA sequencing of the SLC26A4 gene for differential molecular diagnosis of deafness, especially in those patients affected by congenital, progressive and fluctuating mixed hearing loss with bilateral EVA.

  • 16.
    Böttiger, Anna K.
    et al.
    Örebro University, School of Health and Medical Sciences.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health and Medical Sciences.
    Sjöström, Michael
    Yngve, Agneta
    Nilsson, Torbjörn K.
    Örebro University, School of Health and Medical Sciences.
    Association of total plasma homocysteine with methylenetetrahydrofolate reductase genotypes 677C>T, 1298A>C, and 1793G>A and the corresponding haplotypes in Swedish children and adolescents2007In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 19, no 4, p. 659-665Article in journal (Refereed)
    Abstract [en]

    We studied 692 Swedish children and adolescents (aged 9-10 or 15-16 years, respectively), in order to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C, and 1793G>A polymorphisms on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing technology. The MTHFR 677C>T polymorphism was associated with increased tHcy concentrations in both the children and the adolescents (P<0.001 for both age groups) in both genders. The effect of MTHFR 1298A>C was studied separately in subjects with the 677CC and 677CT genotypes, and the 1298C allele was found to be associated with higher tHcy levels both when children were stratified according to 677C>T genotypes, and when using haplotype analyses and diplotype reconstructions. The 1793A allele was in complete linkage disequilibrium with the 1298C allele. It was still possible to show that the 1793A allele was associated with lower tHcy levels, statistically significant in the adolescents. In conclusion, a haplotype-based approach was slightly superior in explaining the genetic interaction on tHcy plasma levels in children and adolescents than a simple genotype based approach (R2 adj 0.44 vs. 0.40). The major genetic impact on tHcy concentrations is attributable to the MTHFR 677C>T polymorphism. The common 1298A>C polymorphism had a minor elevating effect on tHcy, whereas the 1793G>A polymorphism had a lowering effect on tHcy.

  • 17.
    Böttiger, Anna K.
    et al.
    Örebro University, School of Health and Medical Sciences.
    Nilsson, Torbjörn K.
    Henriquez, Patricia
    Serra-Majem, Lluis
    Plasma homocysteine and MTHFR genotypes and haplotypes: gene-nutrient interactions in the Canary Islands Nutrition Study (ENCA)Manuscript (preprint) (Other (popular science, discussion, etc.))
  • 18.
    Castiglione, Alessandro
    et al.
    Department of Neurosciences, Complex Operative Unit of Otorhinolaryngology and Otosurgery, Padua University Hospital, Padua, Italy.
    Guaran, V.
    Bioacoustics Research Laboratory, University of Padua, Padua, Italy.
    Astolfi, L.
    Bioacoustics Research Laboratory, University of Padua, Padua, Italy.
    Orioli, E.
    Department of Medical Sciences, Centre Haemostasis & Thrombosis, Ferrara University, Ferrara, Italy.
    Zeri, G.
    Department of Medical Sciences, Centre Haemostasis & Thrombosis, Ferrara University, Ferrara, Italy.
    Gemmati, D.
    Department of Medical Sciences, Centre Haemostasis & Thrombosis, Ferrara University, Ferrara, Italy.
    Bovo, R.
    Department of Neurosciences, Complex Operative Unit of Otorhinolaryngology and Otosurgery, Padua University Hospital, Padua, Italy.
    Montaldi, A.
    Department of Immunohaematology, Transfusion Medicine and Human Genetics, San Bortolo Hospital, Vicenza, Italy.
    Alghisi, A.
    Department of Immunohaematology, Transfusion Medicine and Human Genetics, San Bortolo Hospital, Vicenza, Italy.
    Martini, A.
    Department of Neurosciences, Complex Operative Unit of Otorhinolaryngology and Otosurgery, Padua University Hospital, Padua, Italy.
    Karyotype-phenotype correlation in partial trisomies of the short arm of chromosome 6: a family case report and review of the literature2013In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 141, no 4, p. 243-259Article, review/survey (Refereed)
    Abstract [en]

    The first child (proband) of nonconsanguineous Caucasian parents underwent genetic investigation because she was affected with congenital choanal atresia, heart defects and kidney hyposplasia with mild transient renal insufficiency. The direct DNA sequencing after PCR of the CHD7 gene, which is thought to be responsible for approximately 60-70% of the cases of CHARGE syndrome/association, found no mutations. The cytogenetic analysis (standard GTG banding karyotype) revealed the presence of extrachromosomal material on 10q. The chromosome analysis was completed with array CGH (30 kb resolution), MLPA and FISH, which allowed the identification of three 6p regions (6p.25.3p23 × 3): 2 of these regions are normally located on chromosome 6, and the third region is translocated to the long arm of chromosome 10. The same chromosomal rearrangement was subsequently found in the father, who was affected with congenital ptosis and progressive hearing loss, and in the proband's sister, the second child, who presented at birth with choanal atresia and congenital heart defects. The mutated karyotypes, which were directly inherited, are thought to be responsible for a variable phenotype, including craniofacial dysmorphisms, choanal atresia, congenital ptosis, sensorineural hearing loss, heart defects, developmental delay, and renal dysfunction. Nevertheless, to achieve a complete audiological assessment of the father, he underwent further investigation that revealed an increased level of the coagulation factor XIII (300% increased activity), fluctuating levels of fibrin D-dimer degradation products (from 296 to 1,587 ng/ml) and a homoplasmic mitochondrial DNA mutation: T961G in the MTRNR1 (12S rRNA) gene. He was made a candidate for cochlear implantation. Preoperative high-resolution computed tomography and magnetic resonance imaging of the temporal bone revealed the presence of an Arnold-Chiari malformation type I. To the best of our knowledge, this study is the second report on partial 6p trisomy that involves the 10q terminal region. Furthermore, we report the first case of documented Arnold-Chiari malformation type I and increased factor XIII activity associated with 6p trisomy. We present a comprehensive report of the familial cases and an exhaustive literature review. 

  • 19.
    Castiglione, Alessandro
    et al.
    Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Padua, Italy.
    Melchionda, Salvatore
    Unit of Medical Genetics, IRCCS, "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy..
    Carella, Massimo
    Unit of Medical Genetics, IRCCS, "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
    Trevisi, Patrizia
    Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Padua, Italy.
    Bovo, Roberto
    Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Padua, Italy.
    Manara, Renzo
    Neuroradiologic Unit, University of Padua, Padua, Italy.
    Martini, Alessandro
    Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Padua, Italy.
    EYA1-related disorders: two clinical cases and a literature review2014In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 78, no 8, p. 1201-1210Article, review/survey (Refereed)
    Abstract [en]

    Objectives: To delineate the diagnostic and rehabilitative aspects of syndromes that have overlapping features, we present the cases of two unrelated Caucasian males affected by hearing impairment, preauricular pits and cervical fistulae. Specific findings that are helpful in the diagnosis and management of EYA1-related disorders are highlighted.

    Methods: Genetic, otologic, imaging, eye and renal evaluations were conducted to achieve a detailed and comprehensive assessment, leading to the most accurate diagnosis and appropriate treatment. A literature review was also carried out.

    Results: Diagnostic criteria indicated that the two patients were affected by BOS1 (Branchio-Otic Syndrome 1). We also identified a novel sporadic missense mutation in the EYA1 gene: p.G533R (c.1597G>A, NM_000503.4), a highly conserved, heterozygotic amino acid substitution. In the other case, we identified the p.X593QextX6 (c.1777T>A, NM_000503.4) substitution. Both variants lead to isoform 1 (EYA1B and EYA1C) which is composed of 592 amino acids. Clinical and in silico evidence suggests a pathogenic role for the new mutations. Imaging evaluation revealed a complex pathology, characterized by external, inner and middle ear malformations, without renal anomalies.

    Conclusions: Our results demonstrate the importance of considering the imaging evaluation and the complete DNA sequencing of the EYA1 gene for the differential diagnosis of deafness and related branchio-oto-renal disorders.

  • 20.
    Chen, Jie
    et al.
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China; Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
    Zhou, Yajing
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
    Sun, Yuhao
    Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China.
    Yuan, Shuai
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Kalla, Rahul
    Edinburgh IBD Science Unit, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
    Sun, Jing
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
    Zhao, Jianhui
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
    Wang, Lijuan
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
    Chen, Xuejie
    Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
    Zhou, Xuan
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
    Dai, Siqi
    Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China.
    Zhang, Yu
    Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China.
    Ho, Gwo-Tzer
    Edinburgh IBD Science Unit, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
    Xia, Dajing
    Department of Toxicology of School of Public Health, & Center of Immunology & Infection, Zhejiang University School of Medicine, Hangzhou, China.
    Cao, Qian
    Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China.
    Liu, Zhanju
    Center for IBD Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
    Larsson, Susanna C.
    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Wang, Xiaoyan
    Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
    Ding, Kefeng
    Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Li, Xue
    Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
    Theodoratou, Evropi
    Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK; Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
    Satsangi, Jack
    Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK.
    Bidirectional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis2023In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 17, no 5, p. 777-785Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Systemic inflammation is well-recognized to be associated with ulcerative colitis (UC), but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence.

    METHODS: We firstly synthesized serum proteomic profiling data from two multi-centered observational studies, in which a panel of systemic inflammatory proteins was analyzed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomization (TSMR) analysis from both forward and reverse directions using five genome-wide association study (GWAS) summary level data for serum proteomic profiles and the largest GWAS of 28,738 European-ancestry individuals for UC risk.

    RESULTS: Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci (cis-pQTLs) or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 (CXCL9) (OR, 1.45, 95% CI, 1.08-1.95, P=.012) and C-C motif chemokine ligand 11 (CCL11) (OR, 1.14, 95%CI: 1.09-1.18, P=3.89×10  -10). Using both cis- and trans-acting pQTLs, an association of caspase-8 (CASP8) (OR, 1.04, 95% CI, 1.03-1.05, P= 7.63×10  -19) was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins.

    CONCLUSIONS: Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

  • 21.
    Du Rietz, Ebba
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Brikell, Isabell
    The National Centre for Register-based Research, Department of Economics and Business Economics, Business and Social Science, Aarhus University, Aarhus, Denmark.
    Butwicka, Agnieszka
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Associations between ADHD and medical disorders in adulthood: a large-scale genetically informed Swedish register study2020In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 50, no 6, p. 452-452Article in journal (Other academic)
    Abstract [en]

    Only a limited number of medical disorders have been thoroughly studied in relation to ADHD, and knowledge is especially lacking for disorders that develop in older ages. This study aimed to map out the phenotypic and aetiologic associations between ADHD and a wide range of medical disorders across adulthood.

    Full- and maternal half-siblings (N = 4,288,451 pairs), aged 18–81 years, were identified from Swedish Population Registers and linked to ICD-diagnoses from National Patient Registers. Logistic regression was used to estimate associations between ADHD and 35 medical disorders (8 disease groups) within-individuals, and across full- and half-siblings. Quantitative genetic modelling was performed to estimate genetic and environmental contributions to the associations with ADHD.

    Adults with ADHD had increased risk for most medical disorders (34/35), showing the strongest associations with nervous system (OR = 3.27) and respiratory (OR = 2.49) disease groups. Significantly (P < 0.001) stronger associations were found between full-siblings than half-siblings for nervous system, respiratory, musculoskeletal and metabolic disease groups. Subsequent quantitative genetic modelling showed that these associations with ADHD were largely explained by shared genetic factors, with the exception for nervous system disorders.

    Individuals with ADHD are at increased risk for a range of medical disorders, with long-term aspects into adult life. While numerous associations between ADHD and medical disorders were largely driven by genetic factors, others, such as nervous system and ageing disorders were mainly driven by individual-specific environmental factors. This mapping of aetiological sources of covariance can guide future research aiming to identify specific mechanisms that contribute to risk for medical disorders in ADHD

  • 22.
    Ellinghaus, David
    et al.
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Jostins, Luke
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Spain, Sarah L.
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Cortes, Adrian
    Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Bethune, Jörn
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Han, Buhm
    Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
    Park, Yu Rang
    Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
    Raychaudhuri, Soumya
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge MA, United States; Division of Genetics, Brigham and Women's Hospital, Boston MA, United States; Division of Rheumatology, Brigham and Women's Hospital, Boston MA, United States.
    Pouget, Jennie G.
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
    Hübenthal, Matthias
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Folseraas, Trine
    Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Cancer Medicine,Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
    Wang, Yunpeng
    Department of Neurosciences, University of California, San Diego, USA.
    Esko, Tonu
    Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Cambridge MA, USA; Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge MA, USA.
    Metspalu, Andres
    Estonian Genome Center, University of Tartu, Tartu, Estonia.
    Westra, Harm-Jan
    Program in Medical and Population Genetics, Broad Institute of mit and Harvard, Cambridge MA, United States; Division of Genetics, Brigham and Women's Hospital, Boston MA, United States; Division of Rheumatology, Brigham and Women's Hospital, Boston MA, United States; Department of Medicine, Harvard Medical School, Boston MA, United States.
    Franke, Lude
    University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, the Netherlands.
    Pers, Tune H.
    Program in Medical and Population Genetics, Broad Institute of mit and Harvard, Cambridge MA, United States; Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge MA, United States; Novo Nordisk Foundation, Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
    Weersma, Rinse K.
    Department of Gastroenterology and Hepatology, University Medical Center, University of Groningen, Groningen, the Netherlands.
    Collij, Valerie
    Department of Gastroenterology and Hepatology, University Medical Center, University of Groningen, Groningen, the Netherlands.
    D'Amato, Mauro
    Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioCruces Health Research Institute, Basque Foundation for Science (Ikerbasque), Bilbao, Spain.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jensen, Anders Boeck
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Lieb, Wolfgang
    Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany; PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany.
    Degenhardt, Franziska
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Forstner, Andreas J.
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Hofmann, Andrea
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    The International IBD Genetics Consortium, (IIBDGC)
    International Genetics of Ankylosing Spondylitis Consortium, (IGAS)
    International PSC Study Group, (IPSCSG)
    Genetic Analysis of Psoriasis Consortium, (GAPC)
    Psoriasis Association Genetics Extension, (PAGE)
    Schreiber, Stefan
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
    Mrowietz, Ulrich
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Juran, Brian D.
    Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester MN, USA.
    Lazaridis, Konstantinos N.
    Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester MN, USA.
    Brunak, Søren
    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Dale, Anders M.
    Department of Neurosciences, University of California, San Diego, USA; Department of Radiology, University of California, San Diego, USA.
    Trembath, Richard C.
    Division of Genetics and Molecular Medicine, King's College London, London, UK.
    Weidinger, Stephan
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Weichenthal, Michael
    Department of Dermatology, University Hospital Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
    Ellinghaus, Eva
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Elder, James T.
    Department of Dermatology, University of Michigan, Ann Arbor, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, USA.
    Barker, Jonathan N. W. N.
    St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.
    Andreassen, Ole A.
    NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway.
    McGovern, Dermot P.
    F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, USA; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
    Karlsen, Tom H.
    Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Cancer Medicine,Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    Parkes, Miles
    Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
    Brown, Matthew A.
    University of Queensland Diamantina Institute, Translational Research Institute, Brisbane QLD, Australia; Institute of Health and Biomedical Innovation (IHBI), Translational Research Institute, Queensland University of Technology (QUT), Brisbane QLD, Australia .
    Franke, Andre
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 5, p. 510-518Article in journal (Refereed)
    Abstract [en]

    We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

  • 23. Ellinghaus, David
    et al.
    Zhang, Hu
    Zeissig, Sebastian
    Lipinski, Simone
    Till, Andreas
    Jiang, Tao
    Stade, Bjoern
    Bromberg, Yana
    Ellinghaus, Eva
    Keller, Andreas
    Rivas, Manuel A.
    Skieceviciene, Jurgita
    Doncheva, Nadezhda T.
    Liu, Xiao
    Liu, Qing
    Jiang, Fuman
    Forster, Michael
    Mayr, Gabriele
    Albrecht, Mario
    Haesler, Robert
    Boehm, Bernhard O.
    Goodall, Jane
    Berzuini, Carlo R.
    Lee, James
    Andersen, Vibeke
    Vogel, Ulla
    Kupcinskas, Limas
    Kayser, Manfred
    Krawczak, Michael
    Nikolaus, Susanna
    Weersma, Rinse K.
    Ponsioen, Cyriel Y.
    Sans, Miquel
    Wijmenga, Cisca
    Strachan, David P.
    McAardle, Wendy L.
    Vermeire, Severine
    Rutgeerts, Paul
    Sanderson, Jeremy D.
    Mathew, Christopher G.
    Vatn, Morten H.
    Wang, Jun
    Noethen, Markus M.
    Duerr, Richard H.
    Buening, Carsten
    Brand, Stephan
    Glas, Juergen
    Winkelmann, Juliane
    Illig, Thomas
    Latiano, Anna
    Annese, Vito
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    D'Amato, Mauro
    Daly, Mark J.
    Nothnagel, Michael
    Karlsen, Tom H.
    Subramani, Suresh
    Rosenstiel, Philip
    Schreiber, Stefan
    Parkes, Miles
    Franke, Andre
    Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies2013In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 145, no 2, p. 339-347Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.

    METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.

    RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.

    CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

  • 24.
    Engström, Karolina
    et al.
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Vánky, Farkas
    Department of Cardiothoracic and Vascular Surgery and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Rehnberg, Malin
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Trinks, Cecilia
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Jonasson, Jon
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Green, Anna
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Gunnarsson, Cecilia
    Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection2020In: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, Vol. 8, no 4, article id e1089Article in journal (Refereed)
    Abstract [en]

    Background: Pathogenic variants in the SMAD3 gene affecting the TGF-beta/SMAD3 signaling pathway with aortic vessel involvement cause Loeys-Dietz syndrome 3, also known as aneurysms-osteoarthritis syndrome.

    Methods: Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis.

    Results: We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co-segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G > C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin-fixed paraffin-embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta.

    Conclusion: A "variant of uncertain significance" according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.

  • 25.
    Ericson, Per G. P.
    et al.
    Department of Bioinformatics and Genetics, Swedish Museum of Natural History, Stockholm, Sweden.
    Irestedt, Martin
    Department of Bioinformatics and Genetics, Swedish Museum of Natural History, Stockholm, Sweden.
    Zuccon, Dario
    Institut de Systématique, Evolution, Biodiversité (ISYEB), UMR7205 CNRS MNHN UPMC EPHE Sorbonne Université, Muséum National d’Histoire Naturelle, Paris, France.
    Larsson, Petter
    Department of Bioinformatics and Genetics, Swedish Museum of Natural History, Stockholm, Sweden; Centre for Palaeogenetics, Stockholm, Swede.
    Tison, Jean-Luc
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Emslie, Steven D.
    Department of Biology and Marine Biology, University of North Carolina, Wilmington NC, USA.
    Götherström, Anders
    Centre for Palaeogenetics, Stockholm, Sweden; Department of Archaeology and Classical Studies, Stockholm University, Stockholm, Sweden.
    Hume, Julian P.
    Bird Group, Department of Life Sciences, Natural History Museum, Tring, Herts, UK.
    Werdelin, Lars
    Department of Palaeobiology, Swedish Museum of Natural History, Stockholm, Sweden.
    Qu, Yanhua
    Department of Bioinformatics and Genetics, Swedish Museum of Natural History, Stockholm, Sweden; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
    A 14,000-year-old genome sheds light on the evolution and extinction of a Pleistocene vulture2022In: Communications Biology, E-ISSN 2399-3642, Vol. 5, no 1, article id 857Article in journal (Refereed)
    Abstract [en]

    The New World Vulture [Coragyps] occidentalis (L. Miller, 1909) is one of many species that were extinct by the end of the Pleistocene. To understand its evolutionary history we sequenced the genome of a 14,000 year old [Coragyps] occidentalis found associated with megaherbivores in the Peruvian Andes. occidentalis has been viewed as the ancestor, or possibly sister, to the extant Black Vulture Coragyps atratus, but genomic data shows occidentalis to be deeply nested within the South American clade of atratus. Coragyps atratus inhabits lowlands, but the fossil record indicates that occidentalis mostly occupied high elevations. Our results suggest that occidentalis evolved from a population of atratus in southwestern South America that colonized the High Andes 300 to 400 kya. The morphological and morphometric differences between occidentalis and atratus may thus be explained by ecological diversification following from the natural selection imposed by this new and extreme, high elevation environment. The sudden evolution of a population with significantly larger body size and different anatomical proportions than atratus thus constitutes an example of punctuated evolution.

  • 26.
    Eriksson, Daniel
    et al.
    Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, Sweden.
    Bianchi, Matteo
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Landegren, Nils
    Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Dalin, Frida
    Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Skov, Jakob
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Hultin-Rosenberg, Lina
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Mathioudaki, Argyri
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Nordin, Jessika
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Hallgren, Åsa
    Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Göran
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Tandre, Karolina
    Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Rantapää Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Söderkvist, Peter
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Rönnblom, Lars
    Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Hulting, Anna-Lena
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Wahlberg, Jeanette
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Endocrinology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Dahlqvist, Per
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Ekwall, Olov
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Meadows, Jennifer R. S.
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
    Bensing, Sophie
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, Sweden.
    Rosengren Pielberg, Gerli
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Kämpe, Olle
    Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, Sweden; K.G. Jebsen Center for Autoimmune Diseases, Bergen, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison’s disease in Sweden2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, no 1, article id 8395Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population. 

  • 27.
    Eriksson, Daniel
    et al.
    Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Røyrvik, Ellen Christine
    Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway.
    Aranda-Guillén, Maribel
    Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
    Berger, Amund Holte
    Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
    Landegren, Nils
    Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Artaza, Haydee
    Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway.
    Hallgren, Åsa
    Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
    Grytaas, Marianne Aardal
    Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
    Ström, Sara
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Bratland, Eirik
    Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
    Botusan, Ileana Ruxandra
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Oftedal, Bergithe Eikeland
    Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway.
    Breivik, Lars
    Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
    Vaudel, Marc
    Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
    Helgeland, Øyvind
    Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway.
    Falorni, Alberto
    Department of Medicine, University of Perugia, Perugia, Italy.
    Jørgensen, Anders Palmstrøm
    Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway.
    Hulting, Anna-Lena
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Svartberg, Johan
    Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.
    Ekwall, Olov
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Fougner, Kristian Johan
    Department of Endocrinology, St. Olavs Hospital, Trondheim, Norway.
    Wahlberg, Jeanette
    Department of Endocrinology, Linköping University, Linköping, Sweden; Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Nedrebø, Bjørn Gunnar
    Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Haugesund Hospital, Haugesund, Norway.
    Dahlqvist, Per
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Knappskog, Per Morten
    Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
    Bøe Wolff, Anette Susanne
    Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway.
    Bensing, Sophie
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Stefan
    Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
    Kämpe, Olle
    Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway; Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
    Husebye, Eystein Sverre
    Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
    GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 959Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2). 

  • 28.
    Eriksson, Lorraine
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Johannesen, Thor Bech
    Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Säll, Olof
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Infectious Diseases.
    Hedberg, Sara Thulin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Fredlund, Hans
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Stegger, Marc
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
    Mölling, Paula
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Genetic variants linked to the phenotypic outcome of invasive disease and carriage of Neisseria meningitidis2023In: Microbial Genomics, E-ISSN 2057-5858, Vol. 9, no 10Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis can be a human commensal in the upper respiratory tract but is also capable of causing invasive diseases such as meningococcal meningitis and septicaemia. No specific genetic markers have been detected to distinguish carriage from disease isolates. The aim here was to find genetic traits that could be linked to phenotypic outcomes associated with carriage versus invasive N. meningitidis disease through a bacterial genome-wide association study (GWAS). In this study, invasive N. meningitidis isolates collected in Sweden (n=103) and carriage isolates collected at Örebro University, Sweden (n=213) 2018-2019 were analysed. The GWAS analysis, treeWAS, was applied to single-nucleotide polymorphisms (SNPs), genes and k-mers. One gene and one non-synonymous SNP were associated with invasive disease and seven genes and one non-synonymous SNP were associated with carriage isolates. The gene associated with invasive disease encodes a phage transposase (NEIS1048), and the associated invasive SNP glmU S373C encodes the enzyme N-acetylglucosamine 1-phosphate (GlcNAC 1-P) uridyltransferase. Of the genes associated with carriage isolates, a gene variant of porB encoding PorB class 3, the genes pilE/pilS and tspB have known functions. The SNP associated with carriage was fkbp D33N, encoding a FK506-binding protein (FKBP). K-mers from PilS, tbpB and tspB were found to be associated with carriage, while k-mers from mtrD and tbpA were associated with invasiveness. In the genes fkbp, glmU, PilC and pilE, k-mers were found that were associated with both carriage and invasive isolates, indicating that specific variations within these genes could play a role in invasiveness. The data presented here highlight genetic traits that are significantly associated with invasive or carriage N. meningitidis across the species population. These traits could prove essential to our understanding of the pathogenicity of N. meningitidis and could help to identify future vaccine targets.

  • 29.
    Faraone, Stephen V.
    et al.
    Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetics of attention deficit hyperactivity disorder2019In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 24, no 4, p. 562-575Article, review/survey (Refereed)
    Abstract [en]

    Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD's high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD's heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD's heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.

  • 30.
    Farkas, Sanja A.
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Vymetalkova, Veronika
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
    Vodickova, Ludmila
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine, Charles University, Pilsen, Czech Republic.
    Vodicka, Pavel
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
    Nilsson, Torbjörn K.
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/beta-catenin signaling pathway genes2014In: Epigenomics, ISSN 1750-1911, Vol. 6, no 2, p. 179-191Article in journal (Refereed)
    Abstract [en]

    Aim: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway.

    Material & methods: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip.

    Results: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes.

    Conclusion: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays.

  • 31.
    Fransén, Karin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Franzén, Petra
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Elmabsout, Ali
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University Hospital.
    Wickbom, Anna
    Örebro University Hospital, Örebro, Sweden.
    Curman, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Törkvist, Leif
    Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, Mauro
    Karolinska University Hospital, Stockholm, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 8, p. e72739-Article in journal (Refereed)
    Abstract [en]

    Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.

  • 32.
    Fransén, Karin
    et al.
    Örebro University, School of Medical Sciences.
    Pettersson, Carolina
    Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hurtig-Wennlöf, Anita
    School of Health and Welfare, Jönköping University, Sweden.
    CRP levels are significantly associated with CRP genotype and estrogen use in The Lifestyle, Biomarker and Atherosclerosis (LBA) study2022In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 22, no 1, article id 170Article in journal (Refereed)
    Abstract [en]

    Background: The C‑reactive protein (CRP) is an important biomarker for atherosclerosis and single nucleotide poly‑morphisms (SNPs) in the CRP locus have been associated with altered CRP levels and associated with risk for cardio‑vascular disease. However, the association between genetic variations in the CRP gene, estrogen use and CRP levels orearly signs of atherosclerosis in young healthy individuals is not fully characterized. We aimed to evaluate the influ‑ence of five genetic variants on both plasma CRP levels and carotid intima‑media thickness (cIMT) values, includingaspects on estrogen containing contraceptive use in females.

    Methods: Genotyping was performed with TaqMan real time PCR and compared with high sensitivity CRP serumlevels in 780 Swedish young, self‑reported healthy individuals. Haplotypes of the SNPs were estimated with the PHASEv 2.1. The cIMT was measured by 12 MHz ultrasound. The contraceptive use was self‑reported.

    Results: Strong associations between CRP and genotype were observed for rs3091244, rs1800947, rs1130864, andrs1205 in women (all p < 0.001). In men, only rs1800947 was associated with CRP (p = 0.029). The independent effectof genotypes on CRP remained significant also after adjustment for established risk factors. Female carriers of the H1/ATGTG haplotype had higher CRP than non‑carriers. This was specifically pronounced in the estrogen‑using group(p < 0.001), and they had also higher cIMT (p = 0.002) than non‑carriers but with a small cIMT difference between thehaplotype groups (0.02 mm). In parallel, a significant correlation between CRP and cIMT in the estrogen using groupwas observed (r = 0.194; p = 0.026).

    Conclusions: Estrogen use, genotypes and haplotypes in the CRP locus are significantly associated with CRP levels.Based on an observed interaction effect between sex/estrogen use and the H1/ATGTG haplotype on CRP, and amarginally thicker cIMT in the estrogen using group, our data suggest that both genotypes and estrogen usage couldbe involved in arterial wall structural differences. The causality between CRP levels and cIMT remains unclear, and theobserved difference in cIMT is not clinically relevant in the present state. Future larger and longitudinal studies mayshed further light on the role of more long‑term estrogen use and early atherosclerosis.

    Download full text (pdf)
    Publisher´s fulltext
  • 33.
    Gkourogianni, Alexandra
    et al.
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden.
    Andrade, Anenisia C.
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden.
    Jonsson, Björn-Anders
    Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
    Segerlund, Emma
    Department of Pediatrics, Sunderby Hospital, Sunderby, Sweden.
    Werner-Sperker, Antje
    Department of Pediatrics, Sunderby Hospital, Sunderby, Sweden.
    Horemuzova, Eva
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm.
    Dahlgren, Jovanna
    Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
    Burstedt, Magnus
    Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden; University Hospital, Örebro, Sweden.
    Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment2020In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 109, no 10, p. 2067-2074Article in journal (Refereed)
    Abstract [en]

    AIM: To explore the phenotype and response to growth hormone in patients with heterozygous-mutations in the insulin-like growth factor I receptor gene (IGF1R).

    METHODS: Children with short-stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analyzed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation dependent probe amplification analysis.

    RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G>T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G>A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26 - 0.60) and 0.64 (range: 0.32 - 0.86) after 1 and 2 years of treatment, respectively.

    CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.

  • 34.
    Götz, Alexandra
    et al.
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tyynismaa, Henna
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Euro, Liliya
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Ellonen, Pekka
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ojala, Tiina
    Department of Pediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Hämäläinen, Riikka H
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tommiska, Johanna
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland g.
    Raivio, Taneli
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Karikoski, Riitta
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tammela, Outi
    Pediatric Research Centre, Tampere University Hospital, Tampere, Finland.
    Simola, Kalle O J
    Genetics Outpatient Clinic, Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Paetau, Anders
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tyni, Tiina
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Suomalainen, Anu
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, no 5, p. 635-642Article in journal (Refereed)
    Abstract [en]

    Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.

  • 35.
    Harris, Simon R.
    et al.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Clarke, Ian N.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Seth-Smith, Helena M. B.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Solomon, Anthony W.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Cutcliffe, Lesley T.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Marsh, Peter
    Health Protection Agency, Public Health Laboratory Southampton, Southampton General Hospital, Southampton, United Kingdom.
    Skilton, Rachel J.
    Molecular Microbiology Group, Southampton General Hospital, University Medical School, Southampton, United Kingdom.
    Holland, Martin J.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Mabey, David
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Peeling, Rosanna W.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Lewis, David A.
    Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Sexually Transmitted Infections Reference Centre, National Health Laboratory Service, National Institute for Communicable Diseases, Johannesburg, South Africa; Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Spratt, Brian G.
    Department of Infectious Disease Epidemiology, St. Mary's Hospital Campus, Imperial College, London, United Kingdom.
    Unemo, Magnus
    Örebro University Hospital. Department of Laboratory Medicine and Clinical Microbiology, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden.
    Persson, Kenneth
    Department of Laboratory Medicine, Clinical Microbiology, Malmö University Hospital, Malmö, Sweden.
    Bjartling, Carina
    Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Malmö University Hospital, Malmö, Sweden.
    Brunham, Robert
    British Columbia Centre for Disease Control, Vancouver BC, Canada.
    de Vries, Henry J. C.
    Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; Sexually Transmitted Infections Outpatient Clinic, Infectious Diseases Cluster, Public Health Service Amsterdam, Amsterdam, Netherlands; Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
    Morré, Servaas A.
    Department of Medical Microbiology of Infection Prevention, Laboratory of Immunogenetics, Vrije University Medical Center, Amsterdam, Netherlands; Department of Genetics and Cell Biology, Institute of Public Health Genomics, University of Maastricht, Maastricht, Netherlands.
    Speksnijder, Arjen
    Geneeskundige en Gezondheidsdienst (GGD), Amsterdam, The Netherlands.
    Bébéar, Cecile M.
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    Clerc, Maite
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    de Barbeyrac, Bertille
    Unité Sous Contrat (USC) Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Université de Bordeaux, Bordeaux, France; USC Mycoplasmal and Chlamydial Infections in Humans, French National Reference Center for Chlamydial Infections, Institut National de la Recherche Agronomique, Bordeaux, France.
    Parkhill, Julian
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Thomson, Nicholas R.
    Pathogen Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 4, p. 413-419Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis is responsible for both trachoma and sexually transmitted infections, causing substantial morbidity and economic cost globally. Despite this, our knowledge of its population and evolutionary genetics is limited. Here we present a detailed phylogeny based on whole-genome sequencing of representative strains of C. trachomatis from both trachoma and lymphogranuloma venereum (LGV) biovars from temporally and geographically diverse sources. Our analysis shows that predicting phylogenetic structure using ompA, which is traditionally used to classify Chlamydia, is misleading because extensive recombination in this region masks any true relationships present. We show that in many instances, ompA is a chimera that can be exchanged in part or as a whole both within and between biovars. We also provide evidence for exchange of, and recombination within, the cryptic plasmid, which is another key diagnostic target. We used our phylogenetic framework to show how genetic exchange has manifested itself in ocular, urogenital and LGV C. trachomatis strains, including the epidemic LGV serotype L2b.

  • 36.
    Heap, Graham A.
    et al.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precis Med, Univ Exeter, Exeter, England.
    Weedon, Michael N.
    Precision medicine, Exeter Medical School, University of Exeter, Exeter, England.
    Bewshea, Claire M.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precision Med Exeter, Univ Exeter, Exeter, England.
    Singh, Abhey
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Chen, Mian
    Oxford Transplant Ctr, Royal Devon & Exeter Hosp, Oxford, England.
    Satchwel, Jack B.
    Oxford Transplant Ctr, Oxford Univ Hosp Natl Hlth Serv NHS Trust, Oxford, England.
    Vivian, Julian P.
    Sch Biomed Sci, Dept Biochem & Mol Biol, Monash Univ, Clayton Vic, Australia.
    So, Kenji
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Dubois, Patrick C.
    Dept Gastroenterol, Kings Coll Hosp, London, England.
    Andrews, Jane M.
    Dept Gastroenterol, IBD Serv, Adelaide SA, Australia; Royal Adelaide Hosp, Univ Adelaide, Adelaide SA, Australia.
    Annese, Vito
    Div Gastroenterol, Azienda Osped, Univ Careggi, Florence, Italy.
    Bampton, Peter
    Flinders Med Ctr, Flinders Univ South Australia, Adelaide SA, Australia.
    Barnardo, Martin
    Oxford Transplant Ctr, Oxford Univ Hosp Natl Hlth Serv NHS Trust, Oxford, England.
    Bell, Sally
    Dept Gastroenterol, St Vincent Hosp, Fitzroy Vic, Australia.
    Cole, Andy
    Royal Derby Hosp, Derby, England.
    Connor, Susan J.
    Dept Gastroenterol & Hepatol, Liverpool Hosp, Sydney NSW, Australia.
    Creed, Tom
    Joint Clin Res Unit, Univ Hosp Bristol NHS Fdn Trust, Bristol, England.
    Cummings, Fraser R.
    Dept Gastroenterol, Univ Hosp Southampton NHS Fdn Trust, Southampton, England.
    D'Amato, Mauro
    Dept Biosci & Nutr, Karolinska Inst, Stockholm, Sweden.
    Daneshmend, Tawfique K.
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England.
    Fedorak, Richard N.
    Div Gastroenterol, Univ Alberta, Edmonton AB, Canada.
    Florin, Timothy H.
    Sch Med, Univ Queensland, South Brisbane Qld, Australia.
    Gaya, Daniel R.
    Gastroenterol Unit, Glasgow Royal Infirm, Glasgow, UK.
    Greig, Emma
    Dept Gastroenterol, Taunton & Somerset NHS Fdn Trust, Taunton, England.
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hart, Alisa
    Dept Med, St Marks Hosp, London, England; Acad Inst, North West London Hosp NHS Trust, London, England.
    Irving, Peter M.
    Dept Gastroenterol, Guys & St Thomas NHS Fdn Trust, London, England.
    Jones, Gareth
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Karban, Amir
    Dept Gastroenterol, Rambam Med Ctr, Haifa, Israel.
    Lawrance, Ian C.
    Ctr Inflammatory Bowel Dis, Fremantle Hosp, Univ Western Australia, Fremantle WA, Australia.
    Lee, James C.
    Dept Gastroenterol, Cambridge Univ Hosp NHS Trust, Cambridge, England.
    Lees, Charlie
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Lev-Tzion, Raffi
    Paediatr Gastroenterol & Nutr Unit, Shaare Zedek Med Ctr, Jerusalem, Israel.
    Lindsay, James
    Dept Gastroenterol, Barts & London NHS Trust, London, England.
    Mansfield, John
    Dept Gastroenterol, Newcastle Univ Hosp NHS Trust, Newcastle NSW, Australia.
    Mawdsley, Joel
    Dept Gastroenterol, West Middlesex Univ Hosp NHS Trust, Isleworth, England.
    Mazhar, Zia
    Dept Gastroenterol, Basildon & Thurrock Hosp NHS Trust, Basildon, England.
    Parkes, Miles
    Dept Gastroenterol, Cambridge Univ Hosp NHS Trust, Cambridge, England.
    Parnell, Kirstie
    Precision Med Exeter, Univ Exeter, Exeter, England.
    Orchard, Timothy R.
    Dept Med, Imperial Coll Healthcare NHS, London, England.
    Radford-Smith, Graham
    Dept Gastroenterol, Royal Brisbane & Womens Hosp, Brisbane Qld, Australia; IBD Grp, Queensland Inst Med Res, Brisbane Qld, Australia; Sch Med, Univ Queensland, Brisbane Qld, Australia.
    Russell, Richard K.
    Dept Paediat Gastroenterol, Yorkhill Hosp, Glasgow, UK.
    Reffitt, David
    Dept Gastroenterol, Lewisham & Greenwich NHS Trust, London, England.
    Satsangi, Jack
    Dept Gastroenterol, Western Gen Hosp, Edinburgh, UK.
    Silverberg, Mark S.
    Zane Cohen Ctr Digest Dis, Inflammatory Bowel Dis Grp, Mt Sinai Hosp, Toronto ON, Canada.
    Sturniolo, Giacomo C.
    Univ Padua, Padua, Italy.
    Tremelling, Mark
    Dept Gastroenterol, Norfolk & Norwich Hosp NHS Trust, Norwich, England.
    Tsianos, Epameinondas V.
    Fac Med, Div Internal Med 1, Univ Ioannina, Ioannina, Greece; Fac Med, Div Gastroenterol, Univ Ioannina, Ioannina, Greece.
    van Heel, David A.
    Barts & London Sch Med & Dent, Blizard Inst, Queen Mary Univ, London, England.
    Walsh, Alissa
    Dept Gastroenterol, St Vincents Hosp, Sydney NSW, Australia.
    Watermeyer, Gill
    Gastrointestinal Clin, Groote Schuur Hosp, Cape Town, South Africa.
    Weersma, Rinse K.
    Dept Gastroenterol & Hepatol, Univ Med Ctr, Groningen, Netherlands; Univ Groningen, Groningen, Netherlands.
    Zeissig, Sebastian
    Dept Internal Med, Univ Med Ctr Schleswig Holstein, Kiel, Germany.
    Rossjohn, Jamie
    Sch Biomed Sci, Dept Biochem & Mol Biol, Monash Univ, Clayton Vic, Australia.
    Holden, Arthur L.
    Int Serious Adverse Events Consortium, Chicago IL, USA.
    Ahmad, Tariq
    IBD Pharmacogenet, Royal Devon & Exeter Hosp, Exeter, England; Precision Med, Univ Exeter, Exeter, England.
    HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 10, p. 1131-1134Article in journal (Refereed)
    Abstract [en]

    Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

  • 37.
    Hong, Eva
    et al.
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Thulin Hedberg, Sara
    Örebro University Hospital. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Abad, Raquel
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Fazio, Cecilia
    Dept Infect Parasites & Immune Mediated Dis, Ist Super Sanita, Rome, Italy.
    Enriquez, Rocio
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Deghmane, Ala-Eddine
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Jolley, Keith A.
    Oxford University, Oxford, England.
    Stefanelli, Paola
    Dept Infect Parasites & Immune Mediated Dis, Ist Super Sanita, Rome, Italy.
    Unemo, Magnus
    Örebro University Hospital. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Vazquez, Julio A.
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Veyrier, Frederic J.
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Taha, Muhamed-Kheir
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Target Gene Sequencing To Define the Susceptibility of Neisseria meningitidis to Ciprofloxacin2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 4, p. 1961-1964Article in journal (Refereed)
    Abstract [en]

    Meningococcal gyrA gene sequence data, MICs, and mouse infection were used to define the ciprofloxacin breakpoint for Neisseria meningitidis. Residue T91 or D95 of GyrA was altered in all meningococcal isolates with MICs of >= 0.064 mu g/ml but not among isolates with MICs of <= 0.032 mu g/ml. Experimental infection of ciprofloxacin-treated mice showed slower bacterial clearance when GyrA was altered. These data suggest a MIC of >= 0.064 mu g/ml as the ciprofloxacin breakpoint for meningococci and argue for the molecular detection of ciprofloxacin resistance.

  • 38.
    Huang, Hailiang
    et al.
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Broad Institute of MIT and Harvard, Cambridge MA, United States.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
    Fine-mapping inflammatory bowel disease loci to single-variant resolution2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 547, no 7662, p. 173-+Article in journal (Refereed)
    Abstract [en]

    Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

  • 39.
    Hur, Yoon-Mi
    et al.
    Department of Education, Mokpo National University, Jeonnam, South Korea.
    Bogl, Leonie H.
    Department of Public Health, University of Helsinki, Helsinki, Finland.
    Ordoñana, Juan R.
    Department of Human Anatomy and Psychobiology and Murcia Institute for Biomedical Research (IMIB-ARRIXACA), University of Murcia, Murcia, Spain.
    Taylor, Jeanette
    Department of Psychology, Florida State University, Tallahassee, FL, USA.
    Hart, Sara A.
    Department of Psychology, Florida State University, Tallahassee, FL, USA.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work.
    Ystrom, Eivind
    PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway; Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
    Dalgård, Christine
    Department of Public Health, Environmental Medicine, and Danish Twin Registry, University of Southern Denmark, Odense, Denmark.
    Skytthe, Axel
    Department of Public Health, and Danish Twin Registry, University of Southern Denmark, Odense, Denmark.
    Willemsen, Gonneke
    Department of Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
    Twin Family Registries Worldwide: An Important Resource for Scientific Research2019In: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 22, no 6, p. 427-437Article in journal (Refereed)
    Abstract [en]

    Much progress has been made in twin research since our last special issue on twin registries (Hur, Y.-M., & Craig, J. M. (2013). Twin Research and Human Genetics, 16, 1-12.). This special issue provides an update on the state of twin family registries around the world. This issue includes 61 papers on twin family registries from 25 countries, of which 3 describe consortia based on collaborations of several twin family registries. The articles included in this issue discuss the establishment and maintenance of twin registries, recruitment strategies, methods of zygosity assessment, research aims and major findings from twin family cohorts, as well as other important topics related to twin studies. The papers amount to approximately 1.3 million monozygotic, dizygotic twins and higher order multiples and their family members who participate in twin studies around the world. Nine new twin family registries have been established across the world since our last issue, which demonstrates that twin registers are increasingly important in studies of the determinants and correlates of complex traits from disease susceptibility to healthy development.

  • 40.
    Huyghe, Jeroen R.
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium; StatUA Statistics Center, University of Antwerp, Antwerp, Belgium.
    Hannula, Samuli
    Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Mäki-Torkko, Elina
    Örebro University, School of Medical Sciences. Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland; Department of Clinical and Experimental Medicine/Technical Audiology, Linköping University, Linköping, Sweden.
    Aikio, Pekka
    Thule Institute, University of Oulu, Oulu, Finland.
    Sorri, Martti
    Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Huentelman, Matthew J.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp,Antwerp, Belgium.
    A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies2011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 3, p. 347-352Article in journal (Refereed)
    Abstract [en]

    The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F(ST) statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F(ST) was smallest for the comparison with the Russians (F(ST)=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.

  • 41.
    Huyghe, Jeroen R.
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Mäki-Torkko, Elina
    Örebro University, School of Medical Sciences. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Lysholm-Bernacchi, Alana
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Aikio, Pekka
    Thule Institute, University of Oulu, Oulu, Finland.
    Stephan, Dietrich A.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Sorri, Martti
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Huentelman, Matthew J.
    Neurogenomics Division, Translational Genomics Research Institute, Phoenix AZ, USA.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, no 5, p. 569-574Article in journal (Refereed)
    Abstract [en]

    The Saami from Fennoscandia are believed to represent an ancient, genetically isolated population with no evidence of population expansion. Theoretical work has indicated that under this demographic scenario, extensive linkage disequilibrium (LD) is generated by genetic drift. Therefore, it has been suggested that the Saami would be particularly suited for genetic association studies, offering a substantial power advantage and allowing more economic study designs. However, no study has yet assessed this claim. As part of a GWAS for a complex trait, we evaluated the relative power for association studies of common variants in the Finnish Saami. LD patterns in the Saami were very similar to those in the non-African HapMap reference panels. Haplotype diversity was reduced and, on average, levels of LD were higher in the Saami as compared with those in the HapMap panels. However, using a 'hidden' SNP approach we show that this does not translate into a power gain in association studies. Contrary to earlier claims, we show that for a given set of common SNPs, genomic coverage attained in the Saami is similar to that in the non-African HapMap panels. Nevertheless, the reduced haplotype diversity could potentially facilitate gene identification, especially if multiple rare variants play a role in disease etiology. Our results further indicate that the HapMap is a useful resource for genetic studies in the Saami.

  • 42.
    Huyghe, Jeroen R.
    et al.
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Van Laer, Lut
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Hendrickx, Jan-Jaap
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium; Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Fransen, Erik
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Demeester, Kelly
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Topsakal, Vedat
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Kunst, Sylvia
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Manninen, Minna
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Jensen, Mona
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Bonaconsa, Amanda
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Mazzoli, Manuela
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Baur, Manuela
    Department of Otorhinolaryngology, University of Tübingen, Tübingen, Germany.
    Hannula, Samuli
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Mäki-Torkko, Elina
    Örebro University, School of Medical Sciences. Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Espeso, Angeles
    Welsh Hearing Institute, Cardiff University, Cardiff, UK.
    Van Eyken, Els
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Flaquer, Antonia
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Becker, Christian
    Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Cologne, Germany.
    Stephens, Dafydd
    Welsh Hearing Institute, Cardiff University, Cardiff, UK.
    Sorri, Martti
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland.
    Orzan, Eva
    Department of Oto-surgery, University Hospital Padova, Padova, Italy.
    Bille, Michael
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Parving, Agnete
    Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
    Pyykkö, Ilmari
    Department of Otorhinolaryngology, University of Tampere, Tampere, Finland.
    Cremers, Cor W. R. J.
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
    Kremer, Hannie
    Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, NL-6500 HB Nijmegen, the Netherlands; Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
    Van de Heyning, Paul H.
    Department of Otorhinolaryngology, University Hospital of Antwerp, Antwerp, Belgium.
    Wienker, Thomas F.
    Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
    Nürnberg, Peter
    Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, D-50674Cologne, Germany.
    Pfister, Markus
    Department of Otorhinolaryngology, University of Tübingen, Tübingen, Germany.
    Van Camp, Guy
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
    Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait2008In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 83, no 3, p. 401-407Article in journal (Refereed)
    Abstract [en]

    Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.

  • 43.
    Ip, Hill F.
    et al.
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boomsma, Dorret I
    Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
    Genetic association study of childhood aggression across raters, instruments, and age2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 413Article in journal (Refereed)
    Abstract [en]

    Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

  • 44.
    Isaksson, Helena S.
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Farkas, Sanja A.
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Müller, Patrick
    Affymetrix core facility at Novum, BEA, Karolinska Institute, Huddinge, Sweden.
    Gustafsson, Dan
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nilsson, Torbjörn, K.
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, no 2, p. 240-251Article in journal (Refereed)
    Abstract [en]

    A child, 2 years with the "hypercalprotectinemia with hyperzincemia" clinical syndrome presented with atypical symptoms and signs, notably persistent fever of around 38°C, thrombocythaemia of >700 x 10(9) /L, and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analyzed whole-genome mRNA expression by the Affymetrix HG U133 PLUS 2.0 array on three occasions 3 to 5 months apart. Major upregulation was demonstrated for the JAK/STAT pathway including in particular CD177, S100A8, S100A9, and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors, and activators, accounting for the febrile apathic state; and the HMBG1 gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic workup of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.

  • 45.
    Johansson, Magnus
    et al.
    Örebro University, School of Medical Sciences.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Maravelia, Panagiota
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Asghar, Naveed
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Caro-Perez, Noelia
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Pasetto, Anna
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sallberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Immunogenicity of a New Flaviviral-Based DNA Launched Suicidal Replicon for Protective Vaccination Against Hepatitis C2019In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 27, no 4, p. 139-139Article in journal (Other academic)
  • 46.
    Jonsson, Lina
    et al.
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Anckarsäter, Henrik
    Departments of Forensic Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.
    Zettergren, Anna
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Westberg, Lars
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Walum, Hasse
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Departments of Forensic Psychiatry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden; Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; RandD Unit, Swedish Prison and Probation Service, Gothenburg, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Melke, Jonas
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Association between ASMT and autistic-like traits in children from a Swedish nationwide cohort2014In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 24, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Individuals with autism spectrum disorders often show low levels of melatonin, and it has been suggested that this decrease may be because of the low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin-synthesis pathway. Also, genetic variants in ASMT have been associated with autism, as well as with low ASMT activity and melatonin levels, suggesting that the low ASMT activity observed in autism may partly be because of variations within the ASMT gene. In this study, we present a symptom-based approach to investigate possible associations between ASMT and autistic-like traits in the general population. To this end, continuous measures of autistic-like traits were assessed in a nationally representative twin cohort (n=1771) from Sweden and six single nucleotide polymorphisms (SNPs), and a duplication of exons 2-8 in ASMT were genotyped. Our results show a nominally significant association, in girls, between one single nucleotide polymorphism (rs5949028) in the last intron of ASMT and social interaction impairments. No significant association, however, was observed with traits related to language impairment or restricted and repetitive behavior. In conclusion, our results support the possible involvement of the ASMT gene in autism spectrum disorders, and our finding that only one of the three traits shows association suggests that genetic research may benefit from adopting a symptom-specific approach to identify genes involved in autism psychopathology.

  • 47.
    Jostins, Luke
    et al.
    Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Halfvarson, Jonas
    Örebro University Hospital. Örebro University, School of Medical Sciences.
    Cho, Judy H.
    Department of Genetics, Yale School of Medicine, New Haven CT, United States; Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven CT, United States.
    Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7422, p. 119-124Article in journal (Refereed)
    Abstract [en]

    Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

  • 48.
    Jørgenrud, Benedicte
    et al.
    Hormone Laboratory, Oslo University Hospital, Oslo, Norway; Hormone Laboratory, Aker Hospital, Oslo, Norway; Division of Women and Children's Health, Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
    Jalanko, Mikko
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Heliö, Tiina
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Jääskeläinen, Pertti
    Heart Center, Kuopio University Hospital, Kuopio, Finland.
    Laine, Mika
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Nieminen, Markku S
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Laakso, Markku
    Department of Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Kuusisto, Johanna
    University of Eastern Finland, Kuopio, Finland; Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
    The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 8, article id e0134184Article in journal (Refereed)
    Abstract [en]

    AIMS: Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters.

    METHODS AND RESULTS: 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation.

    CONCLUSIONS: Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.

  • 49.
    Kaas, A.
    et al.
    Department of Paediatrics, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
    Pfleger, C.
    Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine University, Düsseldorf, Germany.
    Kharagjitsingh, A. V.
    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
    Schloot, N .C.
    Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine University, Düsseldorf, Germany; Medical Faculty, Department of Metabolic Diseases, University of Düsseldorf, Düsseldorf, Germany .
    Hansen, L.
    Department of Paediatrics, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
    Buschard, K.
    Bartholin Institute, Rigshospitalet, Copenhagen, Denmark.
    Koeleman, B. P. C.
    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
    Roep, B. O.
    Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
    Mortensen, H. B.
    Department of Paediatrics, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
    Alizadeh, B. Z.
    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
    Association between age, IL-10, IFN gamma, stimulated C-peptide and disease progression in children with newly diagnosed Type 1 diabetes2012In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 29, no 6, p. 734-741Article in journal (Refereed)
    Abstract [en]

    AIMS: The relation of disease progression and age, serum interleukin 10 (IL-10) and interferon gamma (IFNγ) and their genetic correlates were studied in paediatric patients with newly diagnosed Type 1 diabetes.

    METHODS: Two hundred and twenty-seven patients from the Hvidoere Study Group were classified in four different progression groups as assessed by change in stimulated C-peptide from 1 to 6 months. CA repeat variants of the IL-10 and IFNγ gene were genotyped and serum levels of IL-10 and IFNγ were measured at 1, 6 and 12 months.

    RESULTS: IL-10 decreased (P < 0.001) by 7.7% (1 month), 10.4% (6 months) and 8.6% (12 months) per year increase in age of child, while a twofold higher C-peptide concentration at 1 month (p = 0.06), 6 months (P = 0.0003) and 12 months (P = 0.02) was associated with 9.7%, 18.6% and 9.7% lower IL-10 levels, independent of each other. IL-10 concentrations did not associate with the disease progression groups. By contrast, IFNγ concentrations differed between the four progression groups at 6 and 12 months (P = 0.02 and P = 0.01, respectively); patients with rapid progressing disease had the highest levels at both time points. Distribution of IL-10 and IFNγ genotypes was equal among patients from the progression groups.

    CONCLUSION: IL-10 serum levels associate inversely with age and C-peptide. As age and C-peptide also associate, a triangular association is proposed. Genetic influence on IL-10 production seems to be masked by distinct disease mechanisms. Increased serum IFNγ concentrations associate with rapid disease progression. Functional genetic variants do not associate with a single progression pattern group, implying that disease processes override genetically predisposed cytokine production.

  • 50. Kaminsky, Zachary A.
    et al.
    Tang, Thomas
    Wang, Sun-Chong
    Ptak, Carolyn
    Oh, Gabriel H. T.
    Wong, Albert H. C.
    Feldcamp, Laura A.
    Virtanen, Carl
    Halfvarson, Jonas
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    McRae, Allan F.
    Visscher, Peter M.
    Montgomery, Grant W.
    Gottesman, Irving I.
    Martin, Nicholas G.
    Petronis, Art
    DNA methylation profiles in monozygotic and dizygotic twins2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 2, p. 240-245Article in journal (Refereed)
    Abstract [en]

    Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of approximately 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10(-294)). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

123 1 - 50 of 115
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf