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A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
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2016 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 151, no 4, 724-732 p.Article in journal (Refereed) Published
Abstract [en]

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.
Keyword [en]
Genetics; Inflammatory Bowel Diseases; Microbiota
National Category
Gastroenterology and Hepatology
Identifiers
URN: 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
Funder
Swedish Research Council, 521-2011-2764 VR 2010-2976 VR 2013-3862
Note

Funding Agencies:

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

SUCCESS

Swiss National Science Foundation 146290

Eli and Edythe Broad Foundation IBD-0164R

European Union

Kenneth Rainin Chair for Inflammatory Bowel Disease Research

Leona M and Harry B Helmsley Charitable Trust

National Health and Medical Research Council APP498405

Available from: 2016-10-03 Created: 2016-10-03 Last updated: 2017-01-09Bibliographically approved

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