Role of Glycine Metabolism in Cardiovascular Disease

甘氨酸代谢在心血管疾病中的作用

• 批准号: 9312093
• 负责人: Hooman Allayee
• 金额: $ 80.39万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312093
• 关键词: Address; Alleles; Animal Model; Apolipoprotein E; Architecture; Atherosclerosis; Attenuated; Bioinformatics; Biological; Carbamyl Phosphate; Cardiac; Cardiovascular Diagnostic Techniques; Cardiovascular Diseases; Cause of Death; Cell Adhesion; Clinical; Complement; Data; Data Set; Development; Diet; Dietary Supplementation; Disease; Elderly; Employee Strikes; Endocrine System Diseases; Enzymes; Epidemiology; Estrogen Replacement Therapy; Evaluation; Event; Exhibits; Face; Female; Foam Cells; Foundations; Functional disorder; Genetic; Genetic Determinism; Glycine; Goals; Gonadal Steroid Hormones; Hepatic; Human; Human Genetics; Incidence; Inflammatory; Knowledge; Lead; Lesion; Link; Literature; Measures; Medical Genetics; Meta-Analysis; Metabolism; Morbidity - disease rate; Mus; Myocardial Infarction; Outcome; Pathway interactions; Patients; Plasma; Population; Predisposition; Premature Menopause; Prevalence; Reporting; Risk Factors; Role; Sudden Death; Supplementation; Testing; Variant; Woman; atheroprotective; cardiovascular disorder risk; cohort; dietary manipulation; disease phenotype; disorder risk; experimental study; genetic analysis; genetic approach; genetic association; genome wide association study; genome-wide; genome-wide analysis; mRNA Expression; macrophage; male; men; metabolomics; mortality; mouse model; novel; novel marker; outcome forecast; population based; protein expression; sex; urea cycle

PROJECT SUMMARY Cardiovascular Disease (CVD) is the number one cause of death for both men and women in the US. However, the prevalence of CVD in women at advanced ages actually outnumbers men, and women generally face a worse prognosis following a primary CVD event. Thus, there is a critical need for identifying and understanding the sex-specific biological mechanisms that underlie the development of CVD in order to reduce the morbidity and mortality associated with CVD, particularly in women. In this regard, our recent metabolomics and genetic analyses in a cohort of ~10,000 CVD patients, followed by independent replication in >53,000 subjects, led to the discovery that one of the major genetic determinants of plasma glycine levels is strongly associated with 12% reduced risk of CVD in women (p=6.3x10-5) but not men (p=0.95). The lead variant underlying this striking sex-specific association is located in carbamoyl phosphate synthase 1 (CPS1), which encodes the rate-limiting enzyme in the urea cycle, and the athero-protective allele is associated with increased glycine levels and decreased urea cycle metabolites. This novel finding represents one of the first sexually dimorphic associations reported in the literature for CVD in either men or women, and the magnitude of its effect is equivalent to the most strongly associated loci identified thus far for CVD. However, epidemiological or experimental data directly linking glycine levels with CVD are lacking, and additional studies are needed to prove that glycine metabolism is causally and inversely related to the development of atherosclerosis. The overall goals of our application are to address these fundamentally important gaps in knowledge. We hypothesize that glycine metabolism represents a novel sex-specific, protective, and causal pathway for CVD. To investigate this hypothesis, we propose integrative clinical, genetics, and bioinformatics approaches in human populations, complemented with studies that leverage targeted genetic perturbation and dietary manipulation in animal models. In Specific Aim 1, we will determine the clinical association of glycine- related metabolites with prevalent and incident CVD phenotypes in two independent human cohorts (n>6000), and test whether these associations are modulated by female sex hormones. In parallel, we will conduct the largest meta-analyses of genome-wide association study (GWAS) data to date for these metabolites (n>12,600) and determine whether newly identified loci exhibit sex-specific associations with risk of CVD by leveraging GWAS results from the CARDIoGRAM Consortium (n~185,000). In Specific Aim 2, we will characterize the sex-specific metabolomics profile, atherosclerosis susceptibility, and functional/mechanistic consequences of dietary glycine supplementation or Cps1 deficiency in mice. Taken together, the proposed studies will leverage novel biomarker measures in independent human cohorts, already existing large-scale GWAS data, newly developed mouse models, and ex vivo functional studies to reveal the sexually dimorphic genetic architecture of glycine metabolism and determine its biologically causal relationship with CVD.

项目摘要 心血管疾病（CVD）是美国男性和女性的第一名死亡原因。 但是，高级时代女性的CVD的患病率实际上超过了男性，而女性通常 主要CVD事件后面临更糟糕的预后。因此，识别和 了解CVD发展的基础以减少CVD的基础的性别特异性生物学机制 与CVD相关的发病率和死亡率，尤其是在女性中。在这方面，我们最近的 约有10,000名CVD患者的队列中的代谢组学和遗传分析，然后进行独立复制 在> 53,000名受试者中，发现血浆甘氨酸水平的主要遗传决定因素之一是 与女性的CVD风险降低了12％（p = 6.3x10-5），但男性不相关（p = 0.95）。领先 这种引人注目的性别特异性关联的背后变体位于磷酸盐合酶1（CPS1）， 它在尿素周期中编码限速酶，而动脉保护等位基因与 甘氨酸水平增加并降低尿素周期代谢产物。这个小说的发现代表了第一个 在文献中，男性或女性的CVD文献报道了性二态性关联，幅度 它的作用等效于迄今为止CVD鉴定的最密切相关的基因座。然而， 缺乏将甘氨酸水平与CVD直接联系起来的流行病学或实验数据，还有其他研究 需要证明甘氨酸的代谢与因果关系与成反比 动脉粥样硬化。我们应用的总体目标是解决这些根本重要的差距 知识。我们假设甘氨酸代谢代表了一种新颖的性别特异性，保护性和因果关系 CVD的途径。为了研究这一假设，我们提出了综合临床，遗传学和生物信息学 人类种群的方法，辅以利用靶向遗传扰动和的研究 动物模型中的饮食操纵。在特定目标1中，我们将确定甘氨酸的临床关联 在两个独立人类人群中具有普遍和入射CVD表型的相关代谢物（n> 6000）， 并测试这些关联是否由女性性激素调节。同时，我们将进行 这些代谢产物迄今为止最大的全基因组关联研究（GWAS）数据的最大荟萃分析数据 （n> 12,600），并确定新确定的基因座是否表现出与CVD风险的性别特定关联 利用GWAS是由心脏图联盟（N〜185,000）产生的。在特定的目标2中，我们将 表征性别特异性代谢组学，动脉粥样硬化敏感性和功能/机械 小鼠饮食甘氨酸补充或CPS1缺乏的后果。两者一起，提议 研究将利用独立人类人群中的新型生物标志物测量 GWAS数据，新开发的小鼠模型和离体功能研究以揭示性二态性 甘氨酸代谢的遗传结构，并确定其生物学因果关系与CVD的关系。