Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

Abstract

BACKGROUND & AIMS The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene–smoking interactions) that affect risk for Crohn’s disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD. METHODS We used 55 immunochip-wide data sets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10−/− and Nod2−/− mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription PCR. RESULTS We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P<5.0×10−5; heterogeneity Cochrane Q test P>.05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of IL10-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine, compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wildtype mice exposed to smoke. CONCLUSION In an analysis of 55 immunochip-wide data sets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene–smoking interactions were confirmed in mice with disruption of Il10 and Nod2—variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.

A Proposal for a Study on Treatment Selection and Lifestyle Recommendations in Chronic Inflammatory Diseases: A Danish Multidisciplinary Collaboration on Prognostic Factors and Personalised Medicine

“…A gene-smoking interaction study found that smoking interacted with, for example, NOD2 and IL10 , and seven loci were found to interact differentially with CD and UC (Yadav et al, accepted [66]).…”

Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

“…IBD has a high incidence that affects millions of people globally and the prevalence increases annually . There are many factors thought to lead to the development of colitis, such as age, environment, gender, genetics, and diet . Recent advances in next‐generation sequencing technology have shown that IBD may also result from alterations in the composition and function of gut microbiota, referred to as dysbiosis.…”

Effects of smoking on the association of human leukocyte antigen with ulcerative colitis

“…Given that the risk of UC was significantly increased with former smoking and the low frequency of HLA‐DRB1*15:02 in controls (< 5%), initiating smoking for reducing the risk of UC should not be recommended. Previous studies evaluating HLA–smoking interactions associated with UC in a Caucasian population reported that only the HLA‐DRB3*91:01 allele showed a possible interaction with smoking . However, because of the absence of DRB3 alleles in the Korean panel, we were unable to evaluate the interaction of smoking with HLA‐DRB3.…”