Metabolomics Reveals the Sex-Specific Effects of the SORT1 Low-Density Lipoprotein Cholesterol Locus in Healthy Young Adults

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 he...

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Bibliographic Details
Published in:Journal of proteome research 2014-11, Vol.13 (11), p.5063-5070
Main Authors: Klein, Matthias S, Connors, Kimberly E, Shearer, Jane, Vogel, Hans J, Hittel, Dustin S
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - genetics
Adult
Blood - metabolism
Cardiovascular Diseases - blood
Cardiovascular Diseases - genetics
Cholesterol, LDL - blood
Cholesterol, LDL - genetics
Fatty Acids - blood
Fatty Acids - genetics
Female
Genetic Predisposition to Disease
Heterozygote
Humans
Lipids - blood
Male
Metabolomics - methods
Sex Factors
Young Adult
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Summary: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.
ISSN:1535-3893
1535-3907
DOI:10.1021/pr500659r