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

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.
总结 心血管疾病(CVD)是美国西班牙裔或拉丁裔(H/L)发病和死亡的主要原因 人口。H/L是一个相对年轻的人群,在大多数CVD的风险方面存在较大差异 风险因素,包括肥胖、2型糖尿病(T2 D)、血脂异常和高血压;因此, 预计CVD负担将增加。CVD带来的主要公共卫生和临床挑战 激发了大量的努力,以了解潜在的生物机制-一个关键的障碍,治疗,风险 分层,最终,预防疾病。上千个冠心病基因位点 和心血管疾病的危险因素已被映射通过脂质代谢,血液和心血管疾病的影响, 压力调节,炎症和血小板功能,以及通过仍然未知的机制。 然而,全基因组关联研究(GWAS)的冠心病和中风的H/L人群一直很少见。 事实上,尽管以前对H/L中CVD危险因素的遗传学进行了研究(我们小组有几个),但没有立场- 单独GWAS治疗H/L患者CHD和卒中的研究已发表。因此,对于CHD、中风和CVD危险因素, 基因组学、公共卫生和医学之间的知识差距可以通过丰富基因组学来改善。 翻译管道,其中包括发现CVD相关性状的新位点及其潜在的因果关系, 变异;阐明生物学和/或病理生理学机制;并建立 临床效用和/或对健康结果的影响。我们建议利用H/L个人的现有数据, 大型流行病学和临床生物库研究,并产生新的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。我们的具体目标是(1)发现和 通过对研究的荟萃分析,描述西班牙裔/拉丁裔CVD相关性状的遗传结构 确定了总共超过159,622个H/L参与者;(2)推导出有史以来第一个H/L特异性eQTL图谱, 建立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(发现样本减去测量RNA的参与者:n~ 146,822)和进行 在每项研究中进行全转录组关联研究(TWAS)分析,然后进行荟萃分析 对于每个感兴趣的性状;以及(3)进行共定位并对孟德尔随机化(MR)分析进行采样 确定H/L CVD风险位点中的致病基因,并使用电子健康记录(EHR)相关生物库 通过H/L的表型全关联研究(PheWAS)表征基因座的更广泛临床影响 CVD风险位点。我们的研究具有很高的影响力,因为CVD的负担在西班牙裔/拉丁裔人群中迅速增长 人口趋势表明,到2050年,H/L人口将占美国人口的35%。 我们的研究将确保不同的人群不会是最后一个从精准医疗新时代受益的人群。 与此同时,它开发了将基因组学转化为功能和临床实用性的快速策略。

项目成果

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Lindsay Fernandez-Rhodes其他文献

Lindsay Fernandez-Rhodes的其他文献

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{{ truncateString('Lindsay Fernandez-Rhodes', 18)}}的其他基金

Bio-Social Pathways Linking Socioeconomic Adversity to Obesity
将社会经济逆境与肥胖联系起来的生物社会途径
  • 批准号:
    10732033
  • 财政年份:
    2023
  • 资助金额:
    $ 81.81万
  • 项目类别:

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