Abstract 1581: Gut barrier function-related genes and colorectal cancer risk in Western European populations

Abstract

Abstract The gut barrier is a multi-later system consisting of two main components: 1) a physical barrier comprised of a thick mucus layer and the epithelium providing defense against microbes and foreign antigens, and 2) a mucosal immune system differentiating between pathogenic and commensal microorganisms, and responsible for the immune response to pathogens and pathogen-associated molecular patterns such as lipopolysaccharide (LPS). Gut barrier dysfunction and related inflammation are known to be associated with and contribute to the development and progression of colorectal cancer (CRC). Whether this association is modified by genetic variation in the genes related to intestinal mucosal and immune function has not been well studied in humans. Therefore, we investigated 292 functional and tagging single-nucleotide polymorphisms (SNPs) in 27 genes encoding proteins in the pathways related to endotoxins/LPS sensing and tolerance, inflammation, Crohn’s disease, and colon mucus synthesis in 1,420 incident CRC cases matched 1:1 to control participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Previously measured serum flagellin- and LPS-specific IgA and IgG levels, considered as biomarkers of exposure to bacterial products and intestinal permeability, were available for a subset of matched case-control pairs. Multivariable odds ratios and 95% confidence intervals were calculated using unconditional logistic regression, with Benjamini-Hochberg (BH) adjustment for multiple comparison testing. The adaptive rank-truncated product (ARTP) method implemented in R-package PIGE was used for gene- and pathway-level analyses. Thirty one SNPs in 16 genes related to LPS response and tolerance (TLR4, TNFRSF1B, LBP, CD38, CD14), colon mucosal function (ABCB1, MUC6/MUC2, CAMP/ZNF589), inflammation (ALOX5, IL10, IL12B, IL2/IL21, IL6, NFKB1), and Crohn’s disease (rs3197999, rs762421) were statistically significantly associated with CRC risk (raw P-values < 0.05), but lost significance after correction for multiple testing. Among controls (n = 692), 10 SNPs in 4 genes (ABCB1, MUC6/MUC2, NFKB1, IL1A/IL1B) were statistically significantly associated with biomarkers of intestinal permeability (raw P-values < 0.05; all non-significant after multiple testing correction). Pathway analyses showed no statistically significant effects on CRC risk for either individual genes or genes grouped into distinct pathways. However, the data suggested possible associations between CRC risk and the genes in the LPS pathway (P = 0.18) and genetic variants previously associated with Crohn’s disease (P = 0.08). This large and comprehensive study has identified gut barrier function-related genes and pathways possibly contributing to CRC risk in European populations. Additional studies in large populations and consortia are needed to confirm our findings. Citation Format: Hannah Mandle, Mazda Jenab, David Hughes, Marc Gunter, Elio Riboli, Veronika Fedirko. Gut barrier function-related genes and colorectal cancer risk in Western European populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1581.