Application of a novel polygenic risk score to the study of diabetic cardiomyopathy in diverse populations

新型多基因风险评分在不同人群糖尿病心肌病研究中的应用

基本信息

批准号：
10669753
负责人：
Changwei Li
金额：
$ 12.2万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669753
关键词：
Accounting Adolescence Adult Age Algorithms American Heart Association Articulation Behavior Biological Black race Cardiovascular Diseases Caring Child Childhood Childhood diabetes Classification Clinical Computational algorithm Coronary Artery Risk Development in Young Adults Study Data Data Set Development Diabetes Mellitus Early identification European Functional disorder Genetic Genetic Predisposition to Disease Genetic Risk Genomics Glucose Glycosylated hemoglobin A Health and Retirement Study Heart Heart failure Hispanic Populations Hyperglycemia Incidence Individual Insulin Intervention Left Life Link Linkage Disequilibrium Longevity Measures Mediating Mediation Metabolic Pathway Modeling Molecular Molecular Target Non-Insulin-Dependent Diabetes Mellitus Participant Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Population Population Heterogeneity Predisposition Prevention Prevention strategy Public Health Recommendation Reporting Research Resources Risk Risk Factors Risk Reduction Sampling Serum Societies Testing Trans-Omics for Precision Medicine Ventricular Work biobank biracial cardiovascular risk factor clinical risk clinically significant cohort diabetes risk diabetic cardiomyopathy drug development emerging adult endophenotype fasting plasma glucose follow-up genetic testing genetic variant genome wide association study genome-wide genomic data genomic profiles healthy lifestyle high risk innovation lifestyle intervention metabolome middle age molecular drug target molecular phenotype multi-ethnic multiple omics novel personalized intervention polygenic risk score prevent programs risk prediction statistics young adult

项目摘要

Summary Type 2 diabetes (T2D) is an important risk factor for heart failure (HF) independent of traditional risk factors for cardiovascular disease. However, lowering hemoglobin A1c levels has little effect on reducing HF risk among T2D patients. These findings highlight the importance of primordial prevention strategies to curb T2D-related HF and suggest that pathophysiologic mechanisms independent of hyperglycemia may link these conditions. Hence, molecular phenotyping to better predict T2D and articulate biological pathways relating T2D to HF are critically needed and in line with recommendations by the American Heart Association and Heart Failure Society of America urging further research into the shared genomic susceptibility of these conditions. Recently, a novel genome-wide polygenic risk score (PRS) that combined contributions of millions of genetic variants showed promise for classifying individuals according to T2D status. However, its value for longitudinally predicting the development of T2D from childhood was not assessed and its generalizability was limited to European populations. We hypothesize that a PRS developed using large-scale multi-ancestry genomics datasets will have optimal risk prediction accuracy and be applicable to ancestrally diverse samples. We further hypothesize that the serum metabolomes of individuals with high genetic risk for T2D contain endogenous molecules reflecting mechanisms of diabetic cardiomyopathy, an important T2D-related HF endophenotype. Therefore, the objectives of this proposed study are to develop a PRS to predict T2D risk from early life to midlife and to identify mechanisms underlying diabetes-induced HF. Our PRS will be generated by combining summary statistics from a multi-ethnic GWAS of T2D among more than 1.4 million participants with linkage disequilibrium data from a nationally representative sample of US adults (Aim 1a). Following PRS testing using individual level genomic data from ~600,000 multi-ancestry participants, we will apply our PRS to biracial cohorts of the Bogalusa Heart Study (BHS; n=1,808) and Coronary Artery Risk Development in Young Adults (n=2,341) with measures of glycemic status and glucose lowering medication across the lifespan. Leveraging these unique resources, we will be the first to evaluate the clinical utility of genomic information in the prediction of T2D in childhood and early adulthood (Aim 1b). Finally, we will perform mediation analyses to identify circulating metabolites and metabolic pathways linking genetically elevated T2D risk to subclinical measures of HF leveraging combined sample of 10,929 BHS and the Trans-omics for Precision Medicine program participants (Aim 2). This innovative multi-omics study will likely aid in developing targeted primordial interventions by providing a genomic algorithm to identify individuals at high risk for T2D at an early age and prior to the manifestation of clinical risk factors. Further, our findings may reveal novel molecular mechanisms for diabetic cardiomyopathy, helping to guide pharmaceutical development to treat this condition.

概括 2 型糖尿病 (T2D) 是心力衰竭 (HF) 的一个重要危险因素，独立于传统的心力衰竭危险因素。心血管疾病。然而，降低糖化血红蛋白水平对降低心衰风险影响不大 T2D 患者。这些发现强调了原始预防策略对于遏制 T2D 相关疾病的重要性心力衰竭并表明独立于高血糖的病理生理机制可能将这些病症联系起来。因此，分子表型分析能够更好地预测 T2D 并阐明 T2D 与 HF 相关的生物学途径。迫切需要并符合美国心脏协会和心力衰竭的建议美国学会敦促进一步研究这些疾病的共同基因组易感性。最近，一种新的全基因组多基因风险评分（PRS）结合了数百万遗传因素的贡献变体有望根据 T2D 状态对个体进行分类。然而，它的价值没有评估从儿童时期纵向预测 T2D 的发展，其普遍性仅限于欧洲人群。我们假设 PRS 是使用大规模多祖先开发的基因组学数据集将具有最佳的风险预测准确性，并适用于祖先多样化的样本。我们进一步假设 T2D 高遗传风险个体的血清代谢组包含反映糖尿病心肌病（一种重要的 T2D 相关心力衰竭）机制的内源性分子内表型。因此，本研究的目标是开发 PRS 来预测 T2D 风险早期到中年，并确定糖尿病诱发心力衰竭的机制。我们的 PRS 将由以下方式生成将来自超过 140 万参与者的 T2D 多种族 GWAS 的汇总统计数据与来自美国成年人全国代表性样本的连锁不平衡数据（目标 1a）。遵循 PRS 使用来自约 600,000 名多血统参与者的个体水平基因组数据进行测试，我们将应用我们的 PRS Bogalusa 心脏研究（BHS；n=1,808）的混血儿队列和年轻人冠状动脉风险发展成人 (n=2,341) 在整个生命周期内测量血糖状态和降糖药物。利用这些独特的资源，我们将率先评估基因组信息的临床效用儿童期和成年早期 T2D 的预测（目标 1b）。最后，我们将进行中介分析确定将遗传性升高的 T2D 风险与亚临床相关的循环代谢物和代谢途径利用 10,929 BHS 的组合样本和精准医学跨组学进行 HF 测量计划参与者（目标 2）。这项创新的多组学研究可能有助于开发有针对性的原始通过提供基因组算法来识别早期 T2D 高风险个体的干预措施，在临床危险因素出现之前。此外，我们的发现可能揭示新的分子机制对于糖尿病心肌病，有助于指导治疗这种疾病的药物开发。