A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition
2016 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 151, no 4, 724-732 p.Article in journal (Refereed) Published
Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).
Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.
Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).
Conclusions: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.
Place, publisher, year, edition, pages
Saunders Elsevier, 2016. Vol. 151, no 4, 724-732 p.
Genetics; Inflammatory Bowel Diseases; Microbiota
Gastroenterology and Hepatology
IdentifiersURN: urn:nbn:se:oru:diva-52738DOI: 10.1053/j.gastro.2016.06.051ISI: 000389548500029PubMedID: 27492617ScopusID: 2-s2.0-84989894301OAI: oai:DiVA.org:oru-52738DiVA: diva2:1014704
FunderSwedish Research Council, 521-2011-2764 VR 2010-2976 VR 2013-3862
National Institutes of Health U01DK062413 U01DK062420 U01DK062422 U01DK062429 U01DK062423 U01DK062431 U01DK062432 F30DK098927 P01DK046763 P30CA016042 R01CA141743 R01DK087694 R01DK092235 R01DK098231 R01HS021747 T32DK007180 T32GM007205 U01AI067068 U54DE023798 UL1TR000124
Crohn's and Colitis Foundation of America
Deutsche Forschungsgemeinschaft DFG BR 1912/6-1 Ni575/7-1 Ni 575/4-1
Else Kroner-Fresenius-Stiftung (Else Kroner Exzellenzstipendium) 2010_EKES.32
Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh
Children's Hospital of Philadelphia
Örebro University Hospital Research Foundation
Royal Brisbane and Women's Hospital Research Foundation
Sanford J Grossman Charitable Trust
Swiss National Science Foundation 146290
Eli and Edythe Broad Foundation IBD-0164R
Kenneth Rainin Chair for Inflammatory Bowel Disease Research
Leona M and Harry B Helmsley Charitable Trust
National Health and Medical Research Council APP4984052016-10-032016-10-032017-01-09Bibliographically approved