Leveraging Hispanic/Latino diversity to map and characterize cardiovascular disease loci

利用西班牙裔/拉丁裔多样性来绘制和描述心血管疾病基因座

基本信息

批准号：
10587581
负责人：
Lindsay Fernandez-Rhodes
金额：
$ 81.81万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-16 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587581
关键词：
Address Admixture African ancestry Architecture Asian ancestry Biological Brazil Cardiovascular Diseases Cities Clinical Clinical Data Coronary heart disease Coupled Data Disease Outcome Disparity Dyslipidemias East Asian Electronic Health Record Ensure Epidemiology European Event Gene Expression Gene Expression Regulation Genes Genetic Genetic Predisposition to Disease Genetic study Genomics Genotype Growth Health Hispanic Hispanic Populations Hypertension Individual Inflammation Intervention Investments Knowledge Latin America Latino Latino Population Link Maps Measures Medical Medicine Mendelian randomization Meta-Analysis Mexico Minority Groups Modeling Morbidity - disease rate Native Americans Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Participant Persons Population Population Heterogeneity Prevalence Prospective Studies Public Health Publishing RNA Research Risk Risk Factors Sample Size Sampling Sampling Studies Severity of illness South America Stroke Time Transcript Translating Validation Variant Whole Blood Work barrier to care biobank blood pressure regulation burden of illness cardiovascular disorder risk cardiovascular risk factor causal variant clinically significant disorder prevention epidemiologic data experience genetic architecture genetic risk factor genome wide association study genomic locus improved insight interest lipid metabolism mortality novel phenome platelet function precision medicine predictive modeling risk prediction risk stratification risk variant tool trait transcriptome transcriptome sequencing transcriptomics translational genomics translational pipeline trend

项目摘要

SUMMARY Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among US Hispanic or Latino (H/L) populations. H/Ls are a relatively young population and experience heightened disparities in risk for most CVD risk factors, including obesity, type 2 diabetes (T2D), dyslipidemia, and hypertension; therefore, their absolute CVD burden is expected to increase. The major public health and clinical challenge imposed by CVD has motivated large efforts to understand underlying biologic mechanisms–a critical barrier to treatment, risk stratification, and ultimately, disease prevention. Thousands of genetic loci for coronary heart disease (CHD) and CVD risk factors have been mapped influencing risk of CHD via perturbations of lipid metabolism, blood pressure regulation, inflammation, and platelet function, as well as through mechanisms that remain unknown. Yet, genome-wide association studies (GWAS) for CHD and stroke in H/L populations have been scarce. Indeed, despite previous work on the genetics of CVD risk factors in H/L (several by our group), no stand- alone GWAS for CHD and stroke in H/L has been published. Thus, for CHD, stroke, and CVD risk factors, the knowledge gap between genomics, public health, and medicine could be improved by enriching the genomic translational pipeline, which includes discovering new loci for CVD related traits and their underlying causal variants; elucidating the biological and/or pathophysiological mechanisms; and establishing evidence for clinical utility and/or impact on health outcomes. We propose to leverage extant data on H/L individuals from large epidemiologic and clinical biobank studies and to generate new eQTL data to discover and characterize the genetic architecture of CVD risk and events in H/L populations. Our specific aims are to (1) discover and characterize the genetic architecture of CVD related traits in Hispanic/Latinos through meta-analysis of studies ascertaining more than 159,622 H/L participants in total; (2) derive the first ever H/L-specific eQTL map to build H/L-relevant gene expression prediction models and apply these models to our study samples with genotyping data (discovery sample less the participants with measured RNA: n~146,822) and conduct transcriptome-wide association studies (TWAS) analyses in each individual study followed by meta-analysis for each trait of interest; and (3) perform colocalization and to sample Mendelian Randomization (MR) analyses to identify causal genes amongst H/L CVD risk loci, and use electronic health record (EHR)-linked biobanks to characterize the broader clinical impact of loci via phenome wide association studies (PheWAS) for H/L CVD risk loci. Our study is high impact as the burden of CVD is rapidly growing in Hispanic/Latino populations and demographic trends suggest that the H/L population will constitute ~35% of the US population by 2050. Our research will ensure diverse populations are not the last to benefit from the new era of precision medicine at the same time it develops expedited strategies for translating genomics to function and clinical utility.

概括心血管疾病（CVD）是美国西班牙裔或拉丁裔（H/L）发病率和死亡率的主要原因（H/L）人群。 H/LS是一个相对年轻的人口，大多数CVD的分布越来越高。危险因素，包括肥胖，2型糖尿病（T2D），血脂异常和高血压；因此，他们的绝对预计CVD Burnen将增加。 CVD施加的主要公共卫生和临床挑战已积极地努力了解潜在的生物学机制，这是治疗的关键障碍，风险分层，最终是预防疾病。冠心病（CHD）的数千个遗传位置和CVD风险因素已被映射到通过脂质代谢的扰动，血液的扰动来影响CHD的风险压力调节，注射和血小板功能以及通过尚不清楚的机制。然而，全基因组关联研究（GWAS）在H/L种群中用于CHD和中风。确实，以前关于H/L中CVD危险因素遗传学的任务（我们小组的几项）单独出版了H/L中的CHD和中风的GWA。对于CHD，中风和CVD风险因素，通过丰富基因组，基因组学，公共卫生和医学之间的知识差距可以改善转化管道，其中包括发现针对CVD相关特征的新地方及其基本因果变体；阐明生物学和/或病理生理机制；并建立证据临床公用事业和/或对健康结果的影响。我们建议利用来自H/L个人的数据大型流行病学和临床生物库研究，并生成新的EQTL数据以发现和表征 H/L人群中CVD风险和事件的遗传结构。我们的具体目的是（1）发现和通过研究荟萃分析，表征西班牙裔/拉丁裔CVD相关特征的遗传结构确定总共超过159,622 h/L的参与者；（2）将第一个H/L特异性EQTL映射推导到构建H/L相关基因表达预测模型，并将这些模型应用于我们的研究样本基因分型数据（发现样本少于测量的RNA的参与者：N〜146,822）并进行了在每项研究中进行荟萃分析，全转录组关联研究（TWA）分析对于每个感兴趣的特征；（3）进行共定位并进行样本Mendelian随机分析（MR）分析识别H/L CVD风险基因座之间的因果基因，并使用电子健康记录（EHR）连接的生物库为了表征通过现象广泛关联研究（PHEWAS）对H/L的更广泛的临床影响 CVD风险基因座。我们的研究具有很高的影响人口趋势表明，到2050年，H/L人口将占美国人口的35％。我们的研究将确保潜水员的人口不是从精密医学的新时代中受益的最后一个人口同时，它制定了将基因组学转化为功能和临床实用程序的快速策略。