title: Metabolomics reveals the sex-specific effects of the SORT1 low-density lipoprotein cholesterol locus in healthy young adults.
abstract: Metabolite profiles of individuals possessing either the cardiovascular risk or protective variants of the low-density lipoprotein cholesterol (LDL-C) associated 1p13.3 locus of the SORT1 gene (rs646776) were analyzed. Serum metabolites and lipids were assessed using LC-MS-based metabolomics in a healthy young population (n = 138: 95 males, 43 females). Although no significant differences were observed in the combined cohort, divergent sex effects were identified. Females carrying the protective allele showed increased phosphatidylcholines, very long chain fatty acids (>C20), and unsaturated fatty acids. Unsaturated fatty acids are considered to be protective against cardiovascular disease. In contrast, males carrying the protective allele exhibited decreased long-chain fatty acids (≤C20) and sphingomyelins, which is similarly considered to decrease cardiovascular disease risk. No significant changes in clinically assessed lipids such as LDL-C, high-density lipoprotein (HDL-C), total cholesterol, or triglycerides were observed in females, whereas only LDL-C was significantly changed in males. This indicates that, apart from reducing LDL-C, other mechanisms may contribute to the protective effect of the SORT1 locus. Thus, the analysis of metabolic biomarkers might reveal early disease development that may be overlooked by relying on standard clinical parameters.
authors.affiliation: Faculty of Kinesiology, ‡Department of Biochemistry and Molecular Biology, Faculty of Medicine, and §Department of Biological Sciences, University of Calgary , Calgary, Alberta T2N 1N4, Canada.
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Klein
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Connors
authors.forename: Jane
authors.initials: J
authors.lastname: Shearer
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Vogel
authors.forename: Dustin S
authors.initials: DS
authors.lastname: Hittel
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000328:Adult; D001769:Blood / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood* / Q000235:genetics; D005227:Fatty Acids / Q000097:blood / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D012737:Sex Factors; D055815:Young Adult; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008078:Cholesterol, LDL; D005227:Fatty Acids; D008055:Lipids; D000099183:Sortilin
keywords: LDL-C; Metabolomics; SORT1; cardiovascular disease; cholesterol