Abstract
BACKGROUND: Evidence supports a modest positive association between alcohol intake and pancreatic ductal adenocarcinoma (PDAC); however, knowledge regarding mechanisms underlying the association is scarce. Investigation of lipidomic metabolites may provide mechanistic insights into this association. METHODS: We measured 611 lipid species across 14 lipid classes in serum samples collected up to 24 years before PDAC diagnosis in 2 nested case-control studies (706 matched sets) within American and Finnish cohorts. We conducted cross-sectional analyses using multivariable linear regressions to examine associations between log-transformed self-reported alcohol intake and log-transformed lipid concentrations among controls within each cohort. The identified alcohol-associated lipids in both cohorts were then evaluated for PDAC risk using multivariable conditional logistic regressions and fixed-effects meta-analyses to estimate overall odds ratios across the 2 cohorts. RESULTS: Alcohol intake was associated with 21 lipid species, 11 class-specific fatty acids (FA), 3 total FA, and 1 lipid class at Bonferroni significance thresholds with similar directions of associations in both cohorts. Among them, total pentadecanoic acid (FA15:0) and 7 lipid species-TAG(49:3-FA18:2), TAG(51:3-FA18:2), TAG(49:2-FA18:2), TAG(51:3-FA15:0), TAG(51:2-FA18:2), TAG(51:2-FA15:0), and PC(15:0-18:2)-were inversely associated with alcohol intake and with PDAC risk at false discovery rate <0.10, with overall odds ratios ranging from 0.82 to 0.86, without evidence of heterogeneity by smoking habits. CONCLUSION: Findings from 2 prospective cohorts identified 7 lipid species and 1 FA inversely associated with both alcohol intake and PDAC risk. These results suggest that alcohol intake may be positively associated with PDAC through downregulation of circulating lipids years before PDAC diagnosis.