{"doi":"10.3390/metabo15110730","title":"Sex Modifies Metabolic Pathways Associated with Lipids in Untargeted Metabolomics: The Coronary Artery Risk Development in Young Adults (CARDIA) Study, 2005–2006","abstract":"Background: 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. Methods: 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 p < 0.1, and (3) pathway enrichment analyses to identify metabolic pathways that differed by sex using Fisher’s exact test (FET) p < 0.05. Results: 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. Conclusions: Our findings suggest distinct lipid-associated metabolic activity by sex that points to potential mechanistic pathways.","journal":"Metabolites","year":2025,"id":548419,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9322,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":380800,"name":"Annie Green Howard","orcid":"0000-0003-0837-8166","position":1,"is_corresponding":false},{"id":348580,"name":"Katie A. Meyer","orcid":"0000-0001-7490-5273","position":2,"is_corresponding":false},{"id":274762,"name":"Christy L. Avery","orcid":"0000-0002-1044-8162","position":3,"is_corresponding":false},{"id":11361,"name":"Kari E. North","orcid":"0000-0002-8903-0366","position":4,"is_corresponding":false},{"id":1442113,"name":"Sachin Mhatre","orcid":null,"position":5,"is_corresponding":false},{"id":594939,"name":"Wei Sha","orcid":"0000-0002-5453-859X","position":6,"is_corresponding":false},{"id":267566,"name":"Yuanyuan Li","orcid":"0000-0003-0852-8558","position":7,"is_corresponding":false},{"id":430167,"name":"Blake R. Rushing","orcid":"0000-0002-8662-3270","position":8,"is_corresponding":false},{"id":467073,"name":"Susan Sumner","orcid":"0000-0003-3381-6084","position":9,"is_corresponding":false},{"id":255011,"name":"Xiuxia Du","orcid":"0000-0002-3468-9585","position":10,"is_corresponding":false},{"id":245367,"name":"Cora E. Lewis","orcid":"0000-0002-2301-5796","position":11,"is_corresponding":false},{"id":11272,"name":"Penny Gordon-Larsen","orcid":"0000-0001-5322-4188","position":12,"is_corresponding":false},{"id":275426,"name":"Autumn G. Hullings","orcid":"0000-0003-3400-7887","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:58.530220Z","pmid":"41295316","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}