The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear.
Dr Vibeke Andersen and colleagues from Denmark investigated interactions between genes and smoking that affect risk for Crohn’s disease and ulcerative colitis in a case-only study of patients and in mouse models of IBD.
The research team used 55 Immunochip-wide datasets that included 19,735 IBD cases of known smoking status.
The researchers performed 3 meta-analyses each for Crohn’s disease, ulcerative colitis, and IBD, comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers.
The team 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.
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.
|20 of these variants were located within the HLA region at 6p21|
Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction.
The research team identified 64 single nucleotide polymorphisms for which the association between the single nucleotide polymorphisms, and IBD were modified by smoking behavior.
The team found that 20 of these variants were located within the HLA region at 6p21.
Analysis of classical HLA alleles revealed an interaction with smoking.
The researchers replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for Crohn’s disease.
The team identified 2 variants in the same genomic region that interact with smoking in relation to Crohn’s disease risk.
Approximately 45% of the single nucleotide polymorphisms that interact with smoking were in close vicinity to single nucleotide polymorphisms previously associated with IBD.
Many were located near or within genes that regulate mucosal barrier function and immune tolerance.
The research team observed that smoking modified the disease risk of some variants in opposite directions for Crohn’s disease vs ulcerative colitis.
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.
The researchers found that NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke.
Dr Andersen's team comments, "In an analysis of 55 Immunochip-wide datasets, we identified 64 single nucleotide polymorphisms 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."