Genetic Variation at 19q13.33 confers colorectal cancer risk through the interaction of mucosal expression of FUT2 and plasma vitamin B12 levels

Introduction: Genome-wide association studies have identified a common variant at chr19q13.33 within the FUT2 locus as a determinant of colorectal cancer (CRC) susceptibility, with each risk allele conferring an approximately 7% increase in risk (OR 1.07, P = 6.11E--10). This locus regulates expression of FUT2, a fucosyltransferase involved in 1,2- glycosylation, and has also been associated with circulating vitamin B12 (B12) concentrations in genome-widestudies. Objective: To determine whether FUT2 influences CRC-risk through effects on circulating B12 and to test causal relationships across genetic, experimental, and clinical data. Methods: We performed summary-data-based Mendelian randomisation using FUT2 eQTLs from GTEx colon tissue and genome-wide association data for plasma B12 (Generation Scotland), with mediation analysis estimating the proportion of effect mediated by B12. Causal inference was then tested in vivo using Fut2 knockout and wild-type mice exposed to azoxymethane/dextran sodium sulphate (AOM/DSS), with or without B12 supplementation. Results: Genetically predicted higher FUT2 expression was associated with lower B12 levels ( {beta} = -0.735, SE = 0.110, P = 2.63E-11) and reduced CRC-risk ({beta} = -0.256, SE = 0.058, P = 5.85 E -5). Mediation analysis suggested ~80% of the effect of FUT2 on CRC risk is mediated via B12. In mice, neither Fut2 deficiency nor B12 supplementation alone induced tumours, but both significantly increased tumour burden under chemical carcinogenic challenge, with comparable effect sizes.