Gene-Environment Interactions in Inflammatory Bowel Disease: A Systematic Review

Overview

This systematic review summarizes evidence from 39 studies investigating gene-environment interactions (GXE) in inflammatory bowel disease (IBD). Significant interactions were identified between genetic variants and environmental factors such as smoking and diet, highlighting variant-specific effects on disease risk.

Background

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a multifactorial chronic inflammatory disorder influenced by genetics, environmental exposures, immune response, and microbiome. Over 320 IBD-associated genetic loci have been identified, but they explain only a modest portion of disease variance, which differs across populations. Gene-environment interactions may help explain this missing heritability and the heterogeneity in IBD risk across different ancestries and environmental contexts.

Data Highlights

A total of 4,833 publications were screened, yielding 39 eligible studies, with 17 reporting statistically significant gene-environment interactions. The NOD2-smoking interaction, particularly at variant rs2066847, was most frequently studied in relation to Crohn’s disease risk. Immunochip-wide analyses identified 64 smoking-interacting variants. Gene-diet interactions involved multiple nutritional factors such as fatty acids, selenium, potassium, alcohol, heme iron, and vitamin D interacting with specific genes.

Key Findings

• NOD2 variant rs2066847 shows a variant-specific interaction with smoking increasing Crohn’s disease risk.
• Gene-smoking interactions were identified in IBD risk genes (ATG16L1, IL23R, CALM3), detoxification genes (GSTP1, HMOX1), smoking-associated genes (CHRNA3, CHRNA5, PPP1R3C, BDNF), and inflammatory cytokine IL1B.
• Immunochip-wide analyses revealed 64 genetic variants interacting with smoking exposure.
• Gene-diet interactions were observed between fatty acid intake and CYP4F3/FADS2, serum selenium and SEPHS1/SEPSECS, potassium intake and IL21, alcohol consumption and IL12B, heme iron intake and FCGR2A, and serum vitamin D and VDR.
• The risk conferred by environmental factors varies depending on individual genetic backgrounds, underscoring the complexity of IBD pathogenesis.

Clinical Implications

Understanding gene-environment interactions in IBD can improve risk stratification and enable personalized lifestyle and dietary recommendations based on genetic profiles. This knowledge supports the development of genotype-based clinical trials targeting nutrition and lifestyle modifications to reduce disease risk or progression. Clinicians should consider both genetic and environmental factors when assessing IBD risk and management strategies.

Conclusion

Current evidence highlights the significant role of gene-environment interactions in modulating IBD risk, with smoking and diet being key environmental factors interacting with specific genetic variants. Further genome-wide interaction studies and personalized intervention trials are needed to fully elucidate these complex relationships and translate findings into clinical practice.

References

1. International IBD Genetics Consortium (IIBDGC) -- Genetic loci in IBD
2. Systematic Review 2024 -- Exploring Gene-Environment Interactions in IBD