Hartiala Jaana A, Tang W H Wilson, Wang Zeneng, Crow Amanda L, Stewart Alexandre F R, Roberts Robert, McPherson Ruth, Erdmann Jeanette, Willenborg Christina, Hazen Stanley L, Allayee Hooman
Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.
Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.
Nat Commun. 2016 Jan 29;7:10558. doi: 10.1038/ncomms10558.
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.
最近，源自膳食胆碱和左旋肉碱的代谢产物，如氧化三甲胺和甜菜碱，已被确定为小鼠和人类动脉粥样硬化的新风险因素。我们试图确定与血浆甜菜碱水平相关的遗传因素，并确定它们对冠状动脉疾病（CAD）风险的影响。一项两阶段全基因组关联研究（GWAS）在染色体2q34和5q14.1上确定了两个显著相关的基因座。2q24上的主要变异体（rs715）定位于氨甲酰磷酸合成酶1（CPS1），该酶编码一种线粒体酶，催化尿素循环中的第一个关键反应和限速步骤。Rs715也与尿素循环代谢产物水平降低和血浆甘氨酸水平升高显著相关。值得注意的是，rs715仅在女性中与CAD风险降低存在显著的保护关联。这些结果表明，甘氨酸代谢和/或尿素循环代表了动脉粥样硬化发展中潜在的新的性别特异性机制。
