SLC39A8 missense variant is associated with Crohn's disease but does not have a major impact on gut microbiome composition in healthy subjects

PLoS One. 2019 Jan 31;14(1):e0211328. doi: 10.1371/journal.pone.0211328. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Bacteria / classification*
  • Bacteria / genetics
  • Bacteria / isolation & purification
  • Case-Control Studies
  • Cation Transport Proteins / genetics*
  • Crohn Disease / genetics*
  • DNA, Bacterial / genetics
  • DNA, Ribosomal / genetics
  • Feces / microbiology
  • Female
  • Gastrointestinal Microbiome
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heterozygote
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Phylogeny
  • Principal Component Analysis
  • RNA, Ribosomal, 16S / genetics*
  • Sequence Analysis, DNA / methods*

Substances

  • Cation Transport Proteins
  • DNA, Bacterial
  • DNA, Ribosomal
  • RNA, Ribosomal, 16S
  • SLC39A8 protein, human

Grants and funding

This work was supported by VIDI grants (grant numbers 016.136.308 and 864.13.013 to RKW and JF) from the Netherlands Organization for Scientific Research (NWO). Sequencing of the control cohort was funded by the Dutch Top Institute Food and Nutrition (grant number GH001 to CW); CW is further supported by an ERC advanced grant (grant number ERC-671274) and a Spinoza award (grant number NWO SPI 92-266). AZ holds a Rosalind Franklin fellowship (University of Groningen) and an ERC Starting Grant (grant number ERC-715772). JF and AZ are also supported by a CardioVasculair Onderzoek Nederland (grant number CVON 2012-03).