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

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.

SUBMITTER: Li D

PROVIDER: S-EPMC5037008 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Li Dalin D Achkar Jean-Paul JP Haritunians Talin T Jacobs Jonathan P JP Hui Ken Y KY D'Amato Mauro M Brand Stephan S Radford-Smith Graham G Halfvarson Jonas J Niess Jan-Hendrik JH Kugathasan Subra S Büning Carsten C Schumm L Philip LP Klei Lambertus L Ananthakrishnan Ashwin A Aumais Guy G Baidoo Leonard L Dubinsky Marla M Fiocchi Claudio C Glas Jürgen J Milgrom Raquel R Proctor Deborah D DD Regueiro Miguel M Simms Lisa A LA Stempak Joanne M JM Targan Stephan R SR Törkvist Leif L Sharma Yashoda Y Devlin Bernie B Borneman James J Hakonarson Hakon H Xavier Ramnik J RJ Daly Mark M Brant Steven R SR Rioux John D JD Silverberg Mark S MS Cho Judy H JH Braun Jonathan J McGovern Dermot P B DP Duerr Richard H RH

Gastroenterology 20160801 4

<h4>Background & aims</h4>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).<h4>Methods</h4>Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorp ...[more]

PMID: 27492617

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Project description:BACKGROUND:Gene-microbiome interactions are important in aetiology and pathogenesis of inflammatory bowel disease, a chronic inflammatory disorder of the gastrointestinal tract consisting of Crohn's disease and ulcerative colitis. Scarce studies on gene-microbiome interactions show very little overlap in their results. Therefore, it is of utmost importance that gene-microbiome studies are repeated. We aimed to replicate the association between the SLC39A8 [Thr]391 risk allele and gut microbiome composition in patients with inflammatory bowel disease and healthy controls. METHODS:We collected faecal samples, peripheral blood and extensive phenotype data from 291 patients with inflammatory bowel disease and 476 healthy controls. Carrier status information was obtained from whole exome sequencing data, generated using the Illumina HiSeq. The gut microbiome composition was determined by tag-sequencing the 16S rRNA gene. Associations between carrier status and disease were tested using the Wilcoxon-Mann-Whitney test. Associations between carriers and gut microbiome composition were determined using principal coordinate analyses, variance explained, alpha diversity and additive general linear models in inflammatory bowel disease, healthy controls and all groups combined. RESULTS:Crohn's disease patients were more often carriers of the missense variant (21/171, 12.3%) than controls (30/476, 6.3%) (OR = 2.1, P = 0.01). We could not identify associations between carrier status and overall gut microbiome composition and microbial richness in all tested groups after correcting for potential confounding factors. We did identify 37 different operational taxonomical units to be associated with carrier status among the tested groups. Two of these 37 were identified before in the discovery study. CONCLUSIONS:We could confirm the genetic association of the SLC39A8 [Thr]391 risk allele with Crohn's disease but we could only limited replicate the association in gut microbiome composition. Independent replication of gene-microbiome studies is warranted to identify true biological mechanisms.

Project description:BackgroundThis study aims to characterize, the gut and oral microbiome in Asian subjects with Crohn's disease (CD) using whole genome shotgun sequencing, thereby allowing for strain-level comparison.MethodsA case-control study with age, sex and ethnicity matched healthy controls was conducted. CD subjects were limited to well-controlled patients without oral manifestations. Fecal and saliva samples were collected for characterization of gut and oral microbiome respectively. Microbial DNA were extracted, libraries prepared and sequenced reads profiled. Taxonomic diversity, taxonomic association, strain typing and microbial gene pathway analyses were conducted.ResultsThe study recruited 25 subjects with CD and 25 healthy controls. The oral microbe Streptococcus salivarius was found to be enriched and of concordant strains in the gut and oral microbiome of Crohn's disease subjects. This was more likely in CD subjects with higher Crohn's Disease Activity Index (184.3?±?2.9 vs 67.1?±?82.5, p?=?0.012) and active disease status (Diarrhoea/abdominal pain/blood-in-stool/fever and fatigue) (p?=?0.016). Gut species found to be significantly depleted in CD compared to control (Relative abundance: Median[Range]) include: Faecalibacterium prausnitzii (0.03[0.00-4.56] vs 13.69[5.32-18.71], p?=?0.010), Roseburia inulinivorans (0.00[0.00-0.03] vs 0.21[0.01-0.53], p?=?0.010) and Alistipes senegalensis (0.00[0.00-0.00] vs 0.00[0.00-0.02], p?=?0.029). While Clostridium nexile (0.00[0.00-0.12] vs 0.00[0.00-0.00], p?=?0.038) and Ruminococcus gnavus (0.43[0.02-0.33] vs 0.00[0.00-0.13], p?=?0.043) were found to be enriched. C. nexile enrichment was not found in CD subjects of European descent. Microbial arginine (Linear-discriminant-analysis: 3.162, p?=?0.001) and isoprene (Linear-discriminant-analysis: 3.058, p?<?0.001) pathways were found at a higher relative abundance level in gut microbiome of Crohn's disease.ConclusionsThere was evidence of ectopic gut colonization by oral bacteria, especially during the active phase of CD. Previously studied gut microbial differences were detected, in addition to novel associations which could have resulted from geographical/ethnic differences to subjects of European descent. Differences in microbial pathways provide possible targets for microbiome modification.

Dataset Information

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

Publications

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

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