Metabolomic profiling of genotype-derived ABO blood group, secretor status and Lewis antigens and association with pancreatic ductal adenocarcinoma risk.

The ABO locus is associated with pancreatic ductal adenocarcinoma (PDAC). Potential metabolic mechanisms underlying these associations have not been investigated. We examined associations between genotype-derived ABO blood group (rs505922 and rs8176746) and 1478 pre-diagnostic serum metabolites in 4042 participants from eight nested case-control studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study using linear regression and fixed-effect meta-analysis. We then examined associations between the identified ABO-associated metabolites and PDAC in two nested case-control studies (493 cases, 640 controls) using logistic regression and evaluated metabolite mediation of the ABO-PDAC association. Non-O and A (versus O) blood groups were associated with 13 and 20 metabolites, respectively, at false discovery rate < 0.20, with nine in common. The ABO-associated metabolites, sphingosine (non-O: β = 0.15), aspartate (A: β = -0.11), and aspartylphenylalanine (A: β = -0.16) were positively, and fibrinopeptide B (1-13) (non-O: β = 0.13; A: β = 0.21) was inversely associated with PDAC (P < 0.05). Non-O (OR = 1.50, 95% confidence interval [CI] = 1.16-1.94) and A (OR = 1.46, 95%CI = 1.10-1.92) (versus O) blood groups were associated with PDAC (OR = 0.96-1.07 per SD change log10-metabolite), however none significantly mediated the association between ABO blood group and PDAC. Our results suggest the ABO-associated metabolites are independent risk factors for PDAC.