Lipid biomarkers of habitual alcohol intake and associations with pancreatic cancer risk.

Abstract

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. 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. 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. 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.