Complex host genetics influence the microbiome in inflammatory bowel disease.

Genome Med
Authors
Abstract

BACKGROUND: Human genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease.

METHODS: We obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways.

RESULTS: We identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways.

CONCLUSIONS: These results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts.

Year of Publication
2014
Journal
Genome Med
Volume
6
Issue
12
Pages
107
Date Published
2014
URL
DOI
10.1186/s13073-014-0107-1
PubMed ID
25587358
PubMed Central ID
PMC4292994
Links
Grant list
R01 DK092405 / DK / NIDDK NIH HHS / United States
R01 HG005969 / HG / NHGRI NIH HHS / United States
U54 DE023798 / DE / NIDCR NIH HHS / United States
U54 DK102557 / DK / NIDDK NIH HHS / United States