Systems genomics of metabolic syndrome traits

项目总结 项目3 最近的流行病学研究表明，代谢综合征及其临床成分，肥胖， 高血压、血脂异常和糖耐量受损是常见的，并且与 心血管疾病(CVD)、糖尿病和其他疾病。阐明这一点具有临床意义。 导致其高患病率和特定人群差异的遗传因素。大尺度 全基因组关联研究(GWAS)已经成功地确定了该基因的常见和罕见变异 代谢综合征性状，然而，已识别的变异不能解释这些性状的大部分差异。 此外，以前大多数心血管疾病的GWA都是在欧洲人进行的，对此了解较少 美国快速增长的拉美裔少数族裔代谢性心血管疾病特征的基因组结构 表现出很高的易感性。我们提出了两个具体的目标，将利用全面的基因组 芬兰和墨西哥队列中可用的方法和改进的临床数据，结合 建立了协同的、跨学科的基因组学和血脂和心血管疾病的功能专业知识，PI和 这项PPG拨款的研究人员必须解决人类面临的关键挑战和科学知识差距 遗传学：全基因组关联向机械性洞察和种族意识的缓慢转变 临床应用。项目3非常重视人类脂肪转录组的研究，因为 脂肪是肥胖和其他代谢综合征特征的关键组织。在具体目标1中， 在人类脂肪组织中确定代谢综合征及其组成特征的遗传调节因素 提出有针对性的设计，重点研究1)Kruppel样因子14(KLF14)基因作为一种 复制的多个关键代谢基因的主调节器；2)变异型特异性调节脂质和 3)代谢综合征及其肥胖成因的特定背景基因组调控 组件特性。在具体目标2中，我们的目标是确定双向遗传和表观遗传机制。 在欧洲人和拉美人中，减肥和增重之间的转换。个性化医疗不能 在没有考虑种族的情况下成功实施，使发现的人口特定 遗传差异在评估心血管疾病易感性方面至关重要。实现这些具体目标将 阐明了墨西哥人心血管疾病关键危险因素潜在的遗传和表观遗传机制 欧洲人。

PROJECT SUMMARY Project 3 Recent epidemiological studies demonstrate that the metabolic syndrome and its clinical components, obesity, hypertension, dyslipidemia, and impaired glucose tolerance, are common and strongly associated with cardiovascular disease (CVD), diabetes, and other diseases. It would be clinically significant to elucidate genetic factors that contribute to their high prevalence and population-specific differences. Large scale genome-wide association studies (GWAS) have successfully identified common and rare variants for the metabolic syndrome traits, however, the identified variants do not explain a majority of variance in these traits. Furthermore, most of the previous GWAS of CVD have been performed in Europeans, and less is known about the genomic architecture of the metabolic CVD traits in the rapidly growing Hispanic minority of the U.S. who display a high predisposition. We propose two Specific Aims that will utilize comprehensive genomic approaches and refined clinical data available in the Finnish and Mexican cohorts combined with the established synergic, interdisciplinary genomics and functional expertise of lipids and CVD that the PIs and investigators of this PPG grant possess to tackle the key challenge and scientific knowledge gap of human genetics: the slow conversion of the genome-wide associations into mechanistic insights and ethnicity-aware clinical applications. Project 3 puts heavy emphasis on investigation of human adipose transcriptome, because adipose is an accessible key tissue for obesity and other metabolic syndrome traits. In Specific Aim 1, to identify genetic regulators of the metabolic syndrome and its component traits in human adipose tissue, we propose a targeted design, focusing on the investigation of 1) the Kruppel-like factor 14 (KLF14) gene as a replicated master regulator of multiple critical metabolic genes; 2) variant-specific regulation of the lipid and obesity GWAS loci; and 3) context-specific genomic regulation of the metabolic syndrome and its obesogenic component traits. In Specific Aim 2, we aim to identify genetic and epigenetic mechanisms underlying two-way conversions between weight loss and gain in both Europeans and Latinos. Personalized medicine cannot be implemented successfully without taking into account ethnicity, making the discovery of population-specific genetic differences critically important in assessing CVD susceptibility. Accomplishing these Specific Aims will shed light on the genetic and epigenetic mechanisms underlying key risk factors of CVD in Mexicans and Europeans.