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Meta-Analysis
. 2017 Aug;153(2):550-565.
doi: 10.1053/j.gastro.2017.05.010. Epub 2017 May 12.

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

Affiliations
Free PMC article
Meta-Analysis

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

Pankaj Yadav et al. Gastroenterology. .
Free PMC article

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 datasets 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 polymerase chain reaction.

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 Interleukin 10 (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 wild-type mice exposed to smoke.

Conclusions: In an analysis of 55 Immunochip-wide datasets, 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.

Keywords: Animal Model; Gene−Environment Interaction; Inflammation; Nicotine.

Conflict of interest statement

Conflicts of interest

Vibeke Andersen acknowledges receiving compensation from Merck (MSD) and Janssen as a consultant and advisory board member. The other authors declare that there is no conflict of interest.

Figures

Figure 1
Figure 1. Manhattan plots of six Immunochip-wide meta-analyses highlighting potentially smoking-interacting loci for CD and UC
Panels 1–3 (from top) refer to three different smoking contrasts for CD: never vs ever, never vs current and never vs former. Similarly, panels 4–6 (from top) refer to three different smoking contrasts for UC. The horizontal dashed line indicates the threshold (p=5.0×10−5) for suggestive evidence of gene–smoking interaction. All SNPs included in the analyses complied with the G-E independence assumption underlying the case-only design, leaving 117,694 SNPs for case-only meta-analysis. Top SNPs from Table 2 and the gene context (see Table 2 legend for gene context definition) are shown above the suggestive threshold line (in bold). Manhattan plots for IBD (i.e. CD and UC combined) are provided as Supplementary Figure 1.
Figure 2
Figure 2. Visualization of SNPs identified as interacting with smoking (
Table 2). The odds ratio is shown for all markers with suggestive gene–smoking interaction (p<5.0×10−5); gene context (see Table 2 legend for gene context definition) is provided with each rs-number and chromosome numbers are given in parentheses. The three panels refer to different smoking contrasts, namely never vs ever (top), never vs current (middle) and never vs former (bottom). The square color refers to the IBD type (CD: red, UC: blue, IBD: black), large squares mark meta-analysis (Wald test) p values <5.0×10−5.
Figure 3
Figure 3. Impact of interleukin-10 and Nod2 deficiency on the risk of intestinal inflammation in cigarette smoke-exposed mice
Wild-type (WT) and Il10−/− mice were exposed to cigarette smoke (CS), 5 days a week, over a period of 8 weeks. (A) Changes in body weight. (B) Disease Activity Index. (C) Prolapsus apparition under CS exposure in Il10−/− mice. (D) Colon length. (E) Representative H&E stainings. (F) Histological score. (G) Relative expression level of Ifng gene in the ileal tissue of WT, Nod2-deficient and Il10-deficent mice that were either exposed to CS or not. *p<0.05, ***p<0.001 (Kruskal-Wallis test). Data are representative of two independent experiments.

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