Identification of lipid biomarkers via integrative genomic approaches in Hispanic populations

 描述（由申请人提供）：具有美洲印第安人血统的人群（如墨西哥人）极易患血脂异常，但迄今为止，大多数基因组研究主要集中在欧洲人身上，在最易感人群中留下了很大的生物医学知识缺口。血脂水平异常是心血管疾病（CVD）的主要危险因素，心血管疾病是全球主要死亡原因之一。因此，预防和治疗血脂紊乱的进展具有很高的医学意义，特别是对最脆弱但代表性不足的西班牙裔群体。该项目的目的1是在已知的关键脂质基因LPL及其途径中，以及在我们最近发现的具有美洲印第安人特异性信号的新型lipi基因（如SIK 3和RORA）中鉴定西班牙裔特异性脂质风险变体（Ko et al. 2014 Nature Communications）。为了经济有效地捕获这些基因中的罕见和结构变异，在一个9,000名墨西哥人的队列中，我们将利用分子倒置探针（MIP）进行靶向测序。我们将分别在单个变异水平或常见和罕见变异的聚合水平上进行关联检验，以增加统计功效。基于与约19，000名欧洲人的跨人群比较，墨西哥特异性的风险变体显示出最高的跨物种保护和功能证据，将使用MIP或全外显子组测序在12，000名墨西哥人的单独队列中进行复制。常见和罕见风险变体将通过人体脂质代谢的精细表型分析进行功能验证，包括口服脂肪耐受（OFT）试验、LPL酶活性和APOC III蛋白水平。OFT测试测量餐后脂质清除率，当延迟时变得高度致动脉粥样硬化，导致CVD。所提出的精细表型分析将有助于促进从基因组发现到生物学见解和临床相关性的急需翻译。在目标2中，我们将利用我们先前的RNA测序（RNA-seq）和表达数量性状基因座（eQTL）作图（Ko et al.提交）的经验来分析450个墨西哥脂肪组织转录组，并确定由血脂异常介导的群体特异性转录调控。我们将分别在血脂异常和血脂正常的墨西哥人中绘制eQTL，只使用墨西哥人和欧洲人之间显示等位基因频率差异的变体。这些调节性的墨西哥特异性变体是可能通过转录调节影响脂质代谢的功能候选物。由于最近证实高甘油三酯血症和CVD之间的直接关联，因此非常需要开发新的治疗剂以有效降低血清TG水平。目标1和2都与NHLBI的使命一致，即改善不同族裔群体的心血管疾病医疗保健。我的研究培训计划的最终目标是发现和功能特征人群特异性生物标志物，改善血脂异常的预后，预防和治疗;并增加拉丁美洲人急需的CVD基因组分析，加快CVD的个性化医疗在这个代表性不足但迅速增长的少数民族。

 DESCRIPTION (provided by applicant): Populations with Amerindian origins such as Mexicans are highly predisposed to dyslipidemias but so far most genomic studies have mainly focused on Europeans, leaving a large biomedical knowledge gap in the most susceptible group. Abnormal serum lipid levels are key risk factors for one of the worldwide leading causes of death, cardiovascular disease (CVD). Therefore, advancement in the prevention and treatment of lipid disorders are of high medical significance, especially to the most vulnerable but underrepresented Hispanic groups. The Aim 1 of the project is to identify Hispanic-specific lipid risk variants in the known key lipid genes, LPL and its pathway, as well as in the novel lipi genes with Amerindian-specific signals such as SIK3 and RORA that we recently discovered (Ko et al. 2014 Nature Communications). To cost-effectively capture rare and structural variants in these genes in a cohort of 9,000 Mexicans ascertained for hypertriglyceridemia, we will perform targeted sequencing utilizing molecular inversion probes (MIPs). We will perform association test at the single variant level or in aggregation for common and rare variants, respectively, to increase statistical power. Risk variants that are both Mexican-specific based on the cross-population comparison with ~19,000 Europeans and display the highest cross-species conservation and functional evidence, will be carried forward for replication in a separate cohort of 12,000 Mexicans using MIPs or whole exome sequencing. Common and rare risk variants will be functionally validated via refined phenotyping of lipid metabolism in human, including oral fat tolerant (OFT) test, LPL enzymatic activity, and APOCIII protein levels. The OFT test measures the postprandial lipid clearance rate that when delayed becomes highly atherogenic, leading to CVD. The proposed refined phenotyping will help facilitate the much needed translation from genomic findings to biological insight and clinical relevance. In Aim 2, we will utilize our previos experience with RNA-sequencing (RNA-seq) and expression quantitative trait locus (eQTL) mapping (Ko et al. submitted) to profile 450 Mexican adipose tissue transcriptomes and identify population-specific transcriptional regulation, mediated by dyslipidemias. We will map eQTLs in the dyslipidemic and normolipidemic Mexicans, separately, using only the variants that display allele frequency difference between Mexicans and Europeans. These regulatory, Mexican- specific variants are functional candidates that might influence lipid metabolism via transcriptional regulation. Due to the recently demonstrated direct association between hypertriglyceridemia and CVD, there is a high need to develop new therapeutics to effectively lower serum TG levels. Both Aims 1 and 2 align with the mission of NHLBI to improve the medical care for CVD in diverse ethnic groups. The ultimate goals of my Research Training Plan are to discover and functionally characterize population-specific biomarkers, improving prognosis, prevention, and treatment of dyslipidemias; and to increase much needed genomic analysis of CVD in the Latinos, expediting personalized medicine of CVD in this underrepresented but rapidly growing minority.