Identification of lipid biomarkers via integrative genomic approaches in Hispanic populations

 描述(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，但到目前为止，大多数基因组研究主要集中在欧洲人，在最易感人群中留下了巨大的生物医学知识缺口。血脂水平异常是全球主要死亡原因之一心血管疾病(CVD)的关键危险因素。因此，在预防和治疗血脂紊乱方面取得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。该项目的目标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有信号的新的Lipi基因中，识别拉美裔特有的脂质风险变体(Ko等人。2014自然通讯)。为了经济高效地从9000名确诊为高甘油三酯血症的墨西哥人中捕获这些基因中罕见的结构变异，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量级别或对常见变量和罕见变量进行聚合测试，以增加统计能力。根据与约19,000名欧洲人的跨种群比较，既有墨西哥特有的风险变异，又显示出最高的跨物种保护和功能证据，将在使用MIP或整个外显子组测序的12,000名墨西哥人的单独队列中进行复制。常见和罕见的风险变异将通过人类脂代谢的精细表型进行功能验证，包括口腔脂肪耐量(OFT)测试、LPL酶活性和APOCIII蛋白水平。OFT测试测量了餐后脂质清除率，当延迟时，它会变得高度致动脉粥样硬化，导致心血管疾病。拟议的改进表型将有助于促进从基因组发现到生物学洞察力和临床相关性的迫切需要的转换。在目标2中，我们将利用我们以前在RNA测序(RNA-seq)和表达数量性状基因座(EQTL)定位方面的经验(Ko等人。提交)，以描述450个墨西哥脂肪组织转录本，并确定人群特有的转录调控，由血脂异常介导。我们将分别在血脂异常和血脂正常的墨西哥人中定位eQTL，只使用显示墨西哥人和欧洲人之间等位基因频率差异的变异。这些墨西哥特有的调节性变异体是功能候选，可能通过转录调节影响脂质代谢。由于最近证实了高甘油三酯血症与心血管疾病之间的直接联系，因此迫切需要开发新的治疗方法来有效地降低血清甘油三酯水平。目标1和目标2都符合NHLBI的使命，即改善不同种族群体的心血管疾病的医疗保健。我的研究培训计划的最终目标是发现人群特定的生物标志物并对其进行功能表征，改善血脂异常的预后、预防和治疗；并增加对拉丁裔心血管疾病亟需的基因组分析，在这一人数不足但迅速增长的少数群体中加快心血管疾病的个性化药物治疗。

 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.