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

Date Published: January 31, 2019

Publisher: Public Library of Science

Author(s): Valerie Collij, Floris Imhann, Arnau Vich Vila, Jingyuan Fu, Gerard Dijkstra, Eleonora A. M. Festen, Michiel D. Voskuil, Mark J. Daly, Ramnik J. Xavier, Cisca Wijmenga, Alexandra Zhernakova, Rinse K. Weersma, Benoit Chassaing.


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.

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.

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.

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.

Partial Text

Inflammatory bowel disease (IBD) is a common, chronic disorder of the gastrointestinal tract. Patients with this disease experience periods of inflammation alternated by periods of remission. The most common subgroups of IBD are Crohn’s disease (CD), ulcerative colitis (UC) and inflammatory bowel disease undetermined (IBDU)[1].

The aim of this study was to replicate the finding of Li et al’s association between the SLC39A8 [Thr]391 risk allele and gut microbiome composition in our independent cohort of patients with CD, UC, IBDU and HC, which was 4.5 times larger than the original cohort. This provides an increased power in order to detect true associations between carriers and microbial changes. The SLC39A8 gene is known as a transporter of Zinc [17]. Zinc deficiency has been associated before with a boost of inflammatory responses and with the increase of oxidative stress, indicating the role of Zinc in immune functions [18,19]. The role of Zinc has also been studied in the context of IBD, in which an in vitro study has shown that Zinc affects the integrity of the intestinal mucosa [20]. In our previous study we have shown multiple factors to be associated with the gut microbiome composition in the context of IBD [5]. Given the large effects of the missense variant on the gut microbiome composition observed by the discovery paper, the association of the missense variant to Crohn’s disease and the role of Zinc on the immune system, we hypothesized that this missense variant could also be of influence in the altered gut microbiome composition in IBD we observed earlier [5,13,17–20].

Therefore, we argue that in future gene-microbiome studies much larger sample sizes, more stringent statistical analyses (especially with regard to mean counts of OTUs and correcting for confounding factors), replication in independent cohorts and elaborate descriptions of the methods used are needed to pinpoint genome-microbiome associations in both IBD and HC.




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