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Gastroenterology. 2016 Oct;151(4):724-32. doi: 10.1053/j.gastro.2016.06.051. Epub 2016 Aug 1.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

Author information

1
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
2
Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio.
3
Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
4
Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut.
5
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain.
6
Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany.
7
Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia.
8
Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Orebro, Sweden.
9
Department of Internal Medicine I, University of Ulm, Ulm, Germany; Division of Visceral Surgery and Medicine, Department of Gastroenterology, Inselspital Bern, Bern, Switzerland; Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
10
Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, Georgia.
11
Internal Medicine, Krankenhaus Waldfriede, Berlin, Germany.
12
Department of Public Health Sciences, Biostatistical Laboratory, University of Chicago, Chicago, Illinois.
13
Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
14
Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
15
Université de Montréal, Montréal, Québec, Canada; Hopital Maisonneuve Rosemont, Montréal, Québec, Canada.
16
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
17
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
18
Pathobiology Department, Cleveland Clinic, Cleveland, Ohio.
19
Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University, Munich, Germany.
20
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
21
Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
22
Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Center for Digestive Disease, IBD-unit, Karolinska University Hospital, Stockholm, Sweden.
23
Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
24
Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
25
Department of Plant Pathology and Microbiology, University of California, Riverside, Riverside, California.
26
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
27
Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
28
Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
29
Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
30
Université de Montréal, Montréal, Québec, Canada; Montreal Heart Institute, Montréal, Québec, Canada.
31
Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
32
Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
33
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: duerr@pitt.edu.

Abstract

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.

KEYWORDS:

Genetics; Inflammatory Bowel Diseases; Microbiota

PMID:
27492617
PMCID:
PMC5037008
DOI:
10.1053/j.gastro.2016.06.051
[Indexed for MEDLINE]
Free PMC Article

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