Role of Glycine Metabolism in Cardiovascular Disease

项目总结 心血管疾病(CVD)是美国男性和女性的头号死因。 然而，高龄女性的心血管疾病患病率实际上超过了男性，而且女性普遍如此。 在发生原发心血管事件后，面临更糟糕的预后。因此，迫切需要确定和执行 了解导致心血管疾病发生的特定性别的生物学机制，以减少 与心血管疾病相关的发病率和死亡率，特别是在妇女中。在这方面，我们最近 对约10,000名脑血管病患者进行代谢组学和基因分析，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 女性患心血管疾病的风险降低12%(p=6.3x10-5)，而男性则没有(p=0.95)。领头羊 这种显著的性别特异性关联的潜在变体位于氨基甲酰磷酸合成酶1(CPS1)， 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 甘氨酸水平升高，尿素循环代谢产物减少。这一新发现是最早的 文献中报道的男性或女性心血管疾病的性二型性关联，以及 其效应的大小相当于迄今发现的与心血管疾病最相关的基因座。然而， 缺乏直接将甘氨酸水平与心血管疾病联系起来的流行病学或实验数据，以及更多的研究 需要证明甘氨酸新陈代谢与糖尿病的发生有因果关系且呈负相关。 动脉硬化。我们应用程序的总体目标是解决以下方面的这些根本上的重要差距 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 脑血管病的途径。为了研究这一假设，我们提出了临床、遗传学和生物信息学相结合的观点。 人类群体中的方法，辅之以利用有针对性的遗传扰动和 动物模型中的饮食控制。在特定的目标1中，我们将确定甘氨酸的临床相关性- 在两个独立的人类队列(n&gt；6000)中具有流行和偶发CVD表型的相关代谢物， 并测试这些联系是否受女性性激素的调节。同时，我们会进行 迄今为止对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&gT；12,600)，并通过以下方式确定新发现的基因座是否显示出与心血管疾病风险的性别相关 利用来自CARDIoGRAM联盟(n~185,000)的Gwas结果。在具体目标2中，我们将 描述特定性别的代谢组学特征、动脉粥样硬化易感性和功能/机制 补充甘氨酸或Cps1缺乏对小鼠的影响。总而言之，拟议的 研究将在独立的人类队列中利用新的生物标志物措施，这些队列已经存在大规模 Gwas数据、新开发的小鼠模型和体外功能研究揭示了性别二型性 甘氨酸代谢的遗传结构，并确定其与心血管疾病的生物学因果关系。

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.