Sex Modifies Metabolic Pathways Associated with Lipids in Untargeted Metabolomics: The Coronary Artery Risk Development in Young Adults (CARDIA) Study, 2005–2006

<b>Background</b>: There are differences in lipid metabolism by sex that are relevant for health, but metabolic pathways are not fully understood. We investigated sex differences in cross-sectional associations between metabolic pathways identified using untargeted metabolomics and clinical lipid measures (total cholesterol [TC], triglycerides [TG], and low- and high-density lipoprotein cholesterol [LDL-c; HDL-c]) from blood plasma in the Coronary Artery Risk Development in Young Adults (CARDIA) study (Year 20; 2005-2006). Our objective was to determine whether associations between metabolic pathways and lipid measures differ by sex and to identify pathways that may underlie sex-specific mechanisms of lipid metabolism. <b>Methods</b>: Using data from 2169 participants, (44% women, mean age = 45, 58% White, 42% Black), we used: (1) Orthogonal partial least squares-regression (OPLS-R) to compare variation in TC, TG, LDL-c, and HDL-c explained by metabolites in men vs. women, (2) linear regression to assess sex-modification of associations between 7255 metabolite peaks and lipid measures using false discovery rate (FDR)-corrected <i>p</i> < 0.1, and (3) pathway enrichment analyses to identify metabolic pathways that differed by sex using Fisher's exact test (FET) <i>p</i> < 0.05. <b>Results</b>: We found that: (1) untargeted metabolomic data reflected variation in lipid measures better for men compared to women, (2) associations between metabolite peaks and lipid measures differed by sex, and (3) 8 unique pathways differed by sex, particularly primary bile acid biosynthesis, linoleic acid metabolism, and arginine biosynthesis. <b>Conclusions</b>: Our findings suggest distinct lipid-associated metabolic activity by sex that points to potential mechanistic pathways.