Role of Glycine Metabolism in Cardiovascular Disease

项目摘要 心血管疾病（CVD）是美国男性和女性的头号死因。 然而，在老年妇女中心血管疾病的患病率实际上超过了男子，妇女一般 在原发性CVD事件后面临更差的预后。因此，迫切需要查明和 了解CVD发展的性别特异性生物学机制，以减少 与CVD相关的发病率和死亡率，尤其是女性。在这方面，我们最近 代谢组学和遗传学分析在一个队列的约10,000名心血管疾病患者，随后独立复制 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CVD风险降低12%（p=6.3x10-5）而非男性（p=0.95）密切相关。率先 这种显著的性别特异性关联的基础变体位于氨基甲酰磷酸合酶1（CPS 1）中， 它编码尿素循环中的限速酶，而动脉粥样硬化保护等位基因与 增加甘氨酸水平和减少尿素循环代谢物。这一新发现代表了 文献中报道的男性或女性CVD的性二态性相关， 其作用相当于迄今为止对CVD鉴定的最强相关的基因座。然而，在这方面， 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， 需要证明甘氨酸代谢是因果关系和负相关的发展， 动脉粥样硬化我们的应用程序的总体目标是解决这些根本性的重要差距， 知识我们假设甘氨酸代谢代表了一种新的性别特异性，保护性和因果关系。 CVD的途径。为了研究这一假设，我们提出了整合临床，遗传学和生物信息学 在人群中的方法，辅以利用靶向遗传干扰的研究， 在动物模型中进行饮食控制。在具体目标1中，我们将确定甘氨酸的临床相关性- 在两个独立的人类组群（n>6000）中与流行和偶发CVD表型相关的代谢物， 并测试这些联系是否受到女性性激素的调节。与此同时，我们会进行 迄今为止，这些代谢物的全基因组关联研究（GWAS）数据的最大荟萃分析 （n> 12，600），并通过以下方法确定新鉴定的基因座是否表现出与CVD风险的性别特异性相关性： 利用来自心脏病协会的GWAS结果（n~ 185，000）。在第二阶段，我们将 表征性别特异性代谢组学特征、动脉粥样硬化易感性和功能/机制 饮食甘氨酸补充或Cps 1缺乏的后果。综合考虑， 研究将在独立的人类队列中利用新的生物标志物测量， 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，并确定其与CVD的生物因果关系。

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.