Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD

Shixian Hu, Arnau Vich Vila, Ranko Gacesa, Valerie Collij, Christine Stevens, Jack M Fu, Isaac Wong, Michael E Talkowski, Manuel A Rivas, Floris Imhann, Laura Bolte, Hendrik van Dullemen, Gerard Dijkstra, Marijn C Visschedijk, Eleonora A Festen, Ramnik J Xavier, Jingyuan Fu, Mark J Daly, Cisca Wijmenga, Alexandra ZhernakovaAlexander Kurilshikov, Rinse K Weersma*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

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Samenvatting

OBJECTIVE: Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD.

DESIGN: To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF <5% and exome copy number variations (CNVs) with site frequency <1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics.

RESULTS: We identified 12 mbQTLs, including variants in the IBD-associated genes IL17REL, MYRF, SEC16A and WDR78. For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene MYRF (false discovery rate <0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in CYP2D6, GPR151 and CD160 genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in TNFSF15.

CONCLUSION: This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.

Originele taal-2English
Artikelnummer319706
Pagina's (van-tot)285-296
Aantal pagina's12
TijdschriftGut
Volume70
Nummer van het tijdschrift2
Vroegere onlinedatum10-jul-2020
DOI's
StatusPublished - feb-2021

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