Genome-wide analysis of genetic modifiers of Crohn’s disease and ulcerative colitis risk in response to tobacco smoking

Background Gene-environment interactions (GxE) are fundamental for understanding the mechanisms of human diseases. Tobacco smoking is of particular interest for Inflammatory bowel disease (IBD), as it worsens Crohn's disease (CD) but protects against ulcerative colitis (UC). Here, we systematically examined the genome-wide genetic modifiers of tobacco smoking and analysed functional smoking-dependent expression quantitative trait loci (eQTL) in IBD intestinal tissues.Methods Multiplicative interaction effects of genetic variants and tobacco smoking were estimated and meta-analysed from two independent cohorts (cohort A, N = 990; cohort B, N = 2540). Subsequent separate analyses were conducted for CD and UC to identify opposite interaction. The association between HLA classical alleles/amino acid residues and smoking status was tested. GxE eQTL analysis was performed by combining IBD genotype and mucosal transcriptome data. Colocalisation analysis was conducted to identify the shared loci across the results from genome-wide interaction meta-analysis and the GxE eQTL analysis.Findings A total of 572 candidate independent lead genetic variants with multiplicative interactions with tobacco smoking regarding IBD risk were prioritised at a suggestive significance level (meta-analysis P -5). Thirty genetic loci exhibited noteworthy opposite interactions between CD and UC, implicated genes such as ANKS1B, C7, and PARD3B. HLA-DRβ1 harboured the greatest number of polymorphic residues associated with current smoking in IBD. Significant decrease of the frequency of Leu156 in HLA-A was only observed in UC former smokers but not in CD (FDR Interpretation This study deepens the understanding of complex interactions between tobacco smoking and genetic variants for IBD. As a result, it sheds new light on the genetic contribution to the divergent effects of tobacco smoking on CD and UC risk, which might illuminate the future development of genotype-guided primordial preventive strategies in genetically susceptible individuals.Funding JB acknowledges funding from CSC and University Medical Center Groningen top-up Program. EAMF acknowledges funding from ZonMw.