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. 2025 Jun 4;19(6):jjaf061.
doi: 10.1093/ecco-jcc/jjaf061.

Gene-Environment Interactions in Inflammatory Bowel Disease: A Systematic Review of Human Epidemiologic Studies

Affiliations

Gene-Environment Interactions in Inflammatory Bowel Disease: A Systematic Review of Human Epidemiologic Studies

Jingjing Bai et al. J Crohns Colitis. .

Abstract

Background and aims: Complex gene-environment interaction (GXE) for inflammatory bowel disease (IBD) remains elusive. This systematic review aims to summarize the current evidence of GXE in IBD.

Methods: PubMed, EMBASE, Web of Science, and Scopus were systematically searched from inception through April 30, 2024, to identify publications examining the interaction effect of genetic variants and environmental factors in IBD. All eligible studies were graded using STREGA guideline.

Results: Four thousand eight hundred thirty-three publications were identified and screened, resulting in 39 eligible studies, and 17 studies reported statistically significant interactions. NOD2-smoking interaction was most frequently investigated and showed variant-specific effect at rs2066847 regarding the risk of Crohn's disease. Gene-smoking interactions were further identified in other IBD risk genes (ATG16L1, IL23R, and CALM3), detoxification genes (GSTP1 and HMOX1), smoking-associated genes (CHRNA3, CHRNA5, PPP1R3C, and BDNF), and the inflammatory cytokine (IL1B) through a candidate gene approach. Immunochip-wide interaction analyses yielded 64 smoking interacting variants. Gene-diet interactions were observed across multiple nutritional measures, including fatty acid intake with CYP4F3 and FADS2, serum selenium with SEPHS1 and SEPSECS, potassium intake with IL21, alcohol consumption with IL12B, heme iron intake with FCGR2A, and serum vitamin D with VDR.

Conclusions: Current evidence indicated that the IBD risk conferred by environmental factors can vary among the individuals carrying certain genetic variants. Further efforts, including genome wide environment interaction studies and genotype-based nutrition/lifestyle clinical trials, are needed to unravel the missing heritability influenced by environmental exposures and to construct personalized recommendations of lifestyle/dietary modification based on an individual genetic background.

Keywords: gene-environment interaction; genetics; inflammatory bowel disease.

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Conflict of interest statement

J.B. is supported by the China Scholarship Council (No. 202106210082) and University Medical Center Groningen top-up Program. E.A.M.F. received a Clinical Fellowship from the ZonMw. These sponsors have no role in the data analyses and interpretation.

Figures

Figure 1.
Figure 1.
PRISMA flow diagram of study selection.
Figure 2.
Figure 2.
The global distribution of gene-environment interaction studies in IBD. ANZ IBD consortium, Australia New Zealand IBD Consortium. IG-IBD, Italian Group for the study of Inflammatory Bowel Disease. PRISM study, Prospective registry of patients with IBD at the Massachusetts General Hospital.
Figure 3.
Figure 3.
The overview of gene-environment interaction studies in IBD. The area of the bubbles reflected the sample size of IBD patients included in each study. The orange bubbles are the studies focusing on Gene-smoking/lifestyle interactions. Dark green ones stand for gene-diet interactions. Pink bubbles are for gene-microorganism interaction. Each line represented a gene-environment interaction examined in the individual study. Alan Z. Yang et al. (2022) explored the interactions of 38 candidate environmental exposures and IBD GRS for IBD occurrence. Due to the limited space, only significant interactions were displayed for this study. GRS, Genetic risk score.

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