Identification of lipid biomarkers via integrative genomic approaches in Hispanic populations

通过综合基因组方法鉴定西班牙裔人群的脂质生物标志物

基本信息

批准号：
9222651
负责人：
Arthur Ko
金额：
$ 3.56万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-02 至 2019-02-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222651
关键词：
APOA5 gene Adipose tissue Admixture Affect Alleles Amerindian Apolipoproteins Architecture Attention Attenuated Biological Biological Assay Biological Markers Biopsy Candidate Disease Gene Cardiovascular Diagnostic Techniques Cardiovascular Diseases Cardiovascular system Caring Cause of Death Cholesterol Clinical Code Communication DNA Data Diagnosis Diet Disease Dyslipidemias Economic Burden Environmental Risk Factor Ethnic group European Fatty acid glycerol esters Fibrinogen Frequencies Future Gene Expression Gene Expression Regulation Gene Frequency Genes Genetic Genetic Markers Genetic Transcription Genetic Variation Genomic Segment Genomic approach Genomics Goals Haplotypes High-Throughput Nucleotide Sequencing Hispanics Human Hydrolysis Hypertriglyceridemia Individual Knowledge Latino Lead Lipids Lipoproteins Liver Maps Measures Mediating Medical Medical Economics Medicine Metabolic Clearance Rate Mexican Minority Mission Molecular Morbidity - disease rate National Heart, Lung, and Blood Institute Nature Nonesterified Fatty Acids Obesity Oral Orphan Pathway interactions Phenotype Population Population Heterogeneity Predisposition Prevalence Prevention Proteins Quantitative Trait Loci RNA Splicing RORA gene Research Research Personnel Research Training Risk Factors Serum Signal Transduction Site Socioeconomic Status Testing Therapeutic Transcriptional Regulation Translations Triglycerides Underrepresented Minority United States Variant base cardiovascular risk factor career case control chylomicron remnant clinically relevant cohort cost design ethnic diversity exome sequencing experience follow-up genome wide association study genome-wide high risk hypercholesterolemia improved innovation insight lipid disorder lipid metabolism lipoprotein lipase men mortality novel novel therapeutics obesogenic outcome forecast personalized diagnostics personalized medicine precision medicine public health relevance rare variant receptor risk variant salt-inducible kinase screening skills specific biomarkers subcutaneous targeted sequencing trait transcriptome transcriptome sequencing translational genomics uptake

项目摘要

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.

描述（由申请人提供）：美洲印第安人血统的人群（例如墨西哥人）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，在最易受影响的群体中留下了巨大的生物医学知识空白，异常的血清脂质水平是主要风险。心血管疾病 (CVD) 是全球主要死亡原因之一，因此，预防和治疗脂质紊乱具有重要的医学意义，特别是对于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，以及我们最近发现的具有美洲印第安人特异性信号（例如 SIK3 和 RORA）的新型脂质基因中识别西班牙裔特异性脂质风险变异。发现（Ko 等人，2014 年《自然通讯》），为了经济高效地捕获 9,000 名墨西哥人中被确定患有高甘油三酯血症的基因中的罕见和结构变异，我们我们将利用分子倒置探针（MIP）进行靶向测序，我们将分别对常见和罕见变异进行单变异水平或聚合测试，以提高基于杂交的墨西哥特有的风险变异。 - 与约 19,000 名欧洲人进行人群比较，并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。变异体将通过人体脂质代谢的精细表型进行功能验证，包括口服耐脂（OFT）测试、LPL酶活性和APOCIII蛋白水平。OFT测试测量餐后脂质清除率，该清除率延迟后会变得高度致动脉粥样硬化。 CVD。拟议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转化。在目标 2 中，我们将利用我们之前在 RNA 测序方面的经验。 (RNA-seq) 和表达性状位点 (eQTL) 作图（Ko 等人提交），以定量分析 450 个墨西哥脂肪组织转录组，并鉴定由血脂异常介导的人群特异性转录调控。我们将在血脂异常和血脂正常的墨西哥人中绘制 eQTL。单独地，仅使用墨西哥人和欧洲人之间的等位基因频率差异，这些墨西哥特有的调节变异是可能通过转录调控影响脂质代谢变异的功能候选者。由于最近证明高甘油三酯血症与 CVD 之间存在直接关联，因此迫切需要开发新的治疗方法来有效降低血清 TG 水平，目标 1 和目标 2 都符合 NHLBI 改善不同种族群体 CVD 医疗护理的使命。我的研究培训计划的最终目标是发现人群特异性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，并增加拉丁美洲人急需的 CVD 基因组分析；在这个代表性不足但迅速增长的少数群体中，加快 CVD 的个性化治疗。