Abstract
Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. We sought to identify genetic factors associated with plasma betaine levels and determine their effect on risk of coronary artery disease (CAD). A two-stage genome-wide association study (GWAS) identified two significantly associated loci on chromosomes 2q34 and 5q14.1. The lead variant on 2q24 (rs715) localizes to carbamoyl-phosphate synthase 1 (CPS1), which encodes a mitochondrial enzyme that catalyses the first committed reaction and rate-limiting step in the urea cycle. Rs715 is also significantly associated with decreased levels of urea cycle metabolites and increased plasma glycine levels. Notably, rs715 yield a strikingly significant and protective association with decreased risk of CAD in only women. These results suggest that glycine metabolism and/or the urea cycle represent potentially novel sex-specific mechanisms for the development of atherosclerosis.
Highlights
Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans
Multiple single-nucleotide polymorphisms (SNPs) on chromosome 5q14.1 were significantly associated with plasma betaine levels despite not being in strong linkage disequilibrium (LD) with the lead SNP (Fig. 2a), whereas the association signal on chromosome 2q34 was primarily driven by rs[715] (Fig. 2b)
Based on recent studies in mice and humans implicating cholinederived metabolites in atherosclerosis, the goal of the present study was to identify the genetic determinants of plasma betaine levels in humans and determine their relationship with risk of coronary artery disease (CAD)
Summary
Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. Genome-wide association studies (GWASs) for CAD phenotypes and serum or urinary metabolite levels have provided a catalogue of numerous genetic associations, including variants that are often shown to have pleiotropic effects on multiple metabolites in the same biological pathway[5]. These studies have generally been carried out in an unbiased manner, both from a genetics and metabolomics perspective, and efforts are underway to intersect these high-dimensional data to identify pathways causally related to CAD and other diseases. BMI (kg m À 2) Total cholesterol (mg dl À 1) HDL cholesterol (mg dl À 1) LDL cholesterol (mg dl À 1) Triglycerides (mg dl À 1) Number on statin or aspirin therapy (%)
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