Trans-omics Analysis to Unravel Molecular Underpinnings of Heart, Lung and Blood Disease Risk Factors

摘要 心、肺和血液（HLB）特征，包括血压、肺功能和止血措施， 可以预测发病率和死亡率。了解这些HLB性状的调节对于减少 疾病负担。尽管在过去十年中成功鉴定了与HLB性状相关的遗传变异， 遗传变异如何调节这些特征的潜在机制仍不清楚。循环代谢物， 基因和环境相互作用的最终产物，有望将遗传变异，代谢， 改变HLB性状。已经鉴定出影响循环代谢物的多种遗传变异， 然而，这些代谢相关基因座对HLB性状的作用研究不足。种族差异 HLB性状的分布以及疾病风险是众所周知的，但目前的多组学研究结果在很大程度上是由 欧洲血统。很少有研究考察了代谢对多种族人群HLB性状的影响， 组本申请的总体目标是鉴定与HLB性状相关的代谢特征， 影响多种族人群中循环代谢物的遗传位点，并利用这些发现来识别 调节HLB性状的分子途径。我们建议在五个TOPM队列中进行该项目， 包括社区动脉粥样硬化风险（ARIC）研究，心脏病研究（FHS）， 西班牙裔社区健康研究/拉丁美洲人研究（HCHS/SOL）、杰克逊心脏研究（JHS）和多 动脉粥样硬化的种族研究（梅萨），欧洲裔美国人，非洲裔美国人和西班牙裔美国人的平衡 美国人我们将利用现有全基因组测序（WGS）研究的独特资源 数据，代谢组学概况，多种HLB性状，并利用TOPMed云计算试点分析 计算引擎的Commons。我们的目标是：（1）确定与HLB相关的代谢特征 性状，包括血压，肺功能和止血措施;（2）确定遗传 循环代谢物的决定因素;（3）整合目标1和2组学研究结果，以突出因果关系 与调节HLB性状相关的途径。我们的团队具有独特的优势，因为我们的专业知识， 代谢组分析、基因组学、HLB性状、生物统计学和生物信息学。这项研究的结果将 使持续的科学进步，以了解HLB疾病的病理生理学，直接 对预防和潜在治疗的影响。

ABSTRACT Heart, lung, and blood (HLB) traits, including blood pressure, pulmonary function and measures of hemostasis, can predict morbidity and mortality. Understanding the regulation of these HLB traits is essential to decrease disease burden. Despite successful identification of genetic variants associated HLB traits over the last decade, the underlying mechanism of how genetic variants regulate these traits remains unclear. Circulating metabolites, the ultimate products of gene and environment interaction, holds promise to link genetic variants, metabolic changes to HLB traits. Multiple genetic variants that influence circulating metabolites have been identified, however, the role of these metabolic-related loci on HLB traits is understudied. Ethnic differences in the distribution of HLB traits, as well as disease risk are well-known, but current multi-omic findings are largely driven by European ancestry. Few studies have examined the metabolic influence on HLB traits in multiple ethnic groups. The overall objective of this application is to identify metabolic signatures related to HLB traits and genetic loci influencing circulating metabolites in multi-ethnic populations, and utilize these findings to identify molecular pathways that regulate HLB traits. We propose to conduct this project in five TOPMed cohorts, including the Atherosclerosis Risk in Communities (ARIC) study, the Framingham Heart Study (FHS), the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the Jackson Heart Study (JHS), and the Multi- Ethnic Study of Atherosclerosis (MESA), with a balance of European Americans, African Americans and Hispanic Americans. We will leverage the unique resources from each study on existing whole genome sequencing (WGS) data, metabolome profiles, multiple HLB traits, and utilize the TOPMed Cloud Computing Pilot Analysis Commons for the computational engine. Our aims are: (1) to identify metabolic signatures associated with HLB traits, including blood pressure, pulmonary function and measures of hemostasis; (2) to identify genetic determinants of circulating metabolites; and (3) integrating Aims 1 and 2 omics findings to highlight causal pathways associated with the regulation of HLB traits. Our team is uniquely positioned, given our expertise in metabolome profiling, genomics, HLB traits, biostatistics and bioinformatics. The results of this research will enable continued scientific progress toward an understanding of HLB disease pathophysiology, with direct implications for prevention and potential therapies.