Genetics of Elevated High Density Lipoprotein Cholesterol

描述(申请人提供)：“家族性高脂蛋白血症”或高密度脂蛋白胆固醇(高密度脂蛋白-C)升高的综合征被认为与长寿和预防动脉粥样硬化性心血管疾病有关。家族性高脂蛋白血症的唯一已证实的分子病因学是纯合子胆固醇酯转移蛋白(CETP)缺乏症，这种缺乏症几乎只在日本发现，并导致了药物抑制CETP的概念，将其作为一种提高高密度脂蛋白水平的策略。我们招募了我们认为是现有最大的非日本先证者高密度脂蛋白胆固醇水平的队列及其核心和大家庭，以确定导致高密度脂蛋白胆固醇水平的新的遗传因素。我们将使用Illumina 550K芯片进行高密度全基因组SNP扫描，并利用这些数据进行基于家族的关联测试，以搜索高密度脂蛋白-C QTL。具体目的1.使用Illumina Human Hap550珠芯片平台，对750名高密度脂蛋白胆固醇(HDLc)极高的高加索人病例和1500名高加索人对照(50%)进行全基因组关联研究。数据分析将使用经典的病例对照设计，以确定与极高的高密度脂蛋白-C表型最相关的SNP，并对与极高的高密度脂蛋白-C水平相关的CNV进行额外的分析。在AIM 1的全基因组扫描中，0.5-1%最有希望的SNPs以及捕捉到新的或有意义的CNV的SNPs将在一个独立的高加索病例对照队列中进行基因分型，该队列包括500例病例(第90百分位)和1000例对照(第50百分位)，受试者来自护士健康和健康专业人员后续研究。在HWE检测后，将检测SNP等位基因和基因型与病例对照状态的关联。此外，将对目标1和目标2的病例和对照进行综合分析，并测试与高密度脂蛋白胆固醇病例对照状态的关联性。具体目标3.大约20个基于AIMS 1和2的最有希望的基因/区域将在一个独立的以家庭为基础的队列(250个高密度脂蛋白胆固醇先证者家庭，包括高加索人和非裔美国人先证者/家庭)和以人口为基础的美国样本样本(NHANES III)中进行密集基因分型(n=7159)。在基于家族的样本中，我们将使用数量性状分析和基于家族的关联测试(FBAT)来测试HDLC与SNP等位基因和单倍型的关联。在NHANES III队列中，将使用线性回归来检验SNP等位基因和单倍型与高密度脂蛋白胆固醇水平之间的关联。具体目标4.将使用布罗德、诺华和隆德糖尿病遗传学倡议(高加索糖尿病患者)、弗雷明翰心脏研究(高加索人)和NHLBI护理联盟(非裔美国人)提供的公开表型和全基因组基因数据，查询在AIMS 1-3中被证实与高密度脂蛋白-C相关的基因/区域。此外，由于弗雷明翰心脏研究和护理中心的受试者通常有很长一段时间的跟踪观察，因此还将确定这些基因/区域与心血管结果的关联。我们假设，我们的GWA方法将有助于识别导致或易患高密度脂蛋白的新基因，为提高高密度脂蛋白的治疗产生新的靶点。公共卫生相关性：我们将使用Illumina 550K芯片进行高密度全基因组SNP扫描。我们假设，我们的GWA方法将有助于识别导致或易患高密度脂蛋白的新基因，为提高高密度脂蛋白的治疗产生新的靶点。

DESCRIPTION (provided by applicant): The syndrome of "familial hyperalphalipoproteinemia," or elevated high density lipoprotein cholesterol (HDL-C), is known to be associated with longevity and protection from atherosclerotic cardiovascular disease. The only proven molecular etiology of familial hyperalphalipoproteinemia is homozygous cholesteryl ester transfer protein (CETP) deficiency, which is found almost exclusively in Japan and led to the concept of pharmacologic CETP inhibition as a strategy to raise HDL-C levels. We have recruited what we believe to be the largest existing cohort of non-Japanese probands with high HDL-C cholesterol levels and their nuclear and extended families in order to determine novel genetic factors that cause elevated HDL-C. We will perform a high density genome-wide SNP scan using the Illumina 550K chip and utilize these data for family-based tests of association to search for HDL-C QTL. Specific Aim 1. A genome-wide association study will be performed on 750 Caucasian cases with extreme high HDL-C and 1500 Caucasian controls (<50th percentile) using the Illumina HumanHap550 BeadChip platform. Data analysis will be performed using a classic case-control design to identify the SNPs most strongly associated with the extreme high HDL-C phenotype with additional analysis to assess for CNVs associated with extremely high HDL-C levels. Specific Aim 2. 0.5-1% of the most promising SNPs from the genome-wide scan in Aim 1 as well as SNPs capturing novel or significant CNVs will be genotyped in an independent Caucasian case-control cohort of 500 cases ( > 90th percentile) and 1000 controls (<50th percentile) with subjects drawn from the Nurses Health and Health Professionals Follow-up studies. After HWE testing, association of SNP alleles and genotypes with case-control status will be tested. In addition, combined analysis of cases and controls from Aim 1 and Aim 2 will be performed and association with HDL-C case-control status will be tested. Specific Aim 3. Approximately 20 of the most promising genes/regions based on Aims 1 and 2 will be densely genotyped in an independent family-based cohort (250 families of extremely high HDL-C probands, including both Caucasian and African-American probands/families) and in population-based sample representative of the U.S. (NHANES III) comprised of whites, non-Hispanic blacks, and Mexican Americans (n=7159). In the family-based sample, we will test for association of HDL-C with SNP alleles and haplotypes using a quantitative trait analysis and the family-based association test (FBAT). In the NHANES III cohort, linear regression will be used to test for association between SNP alleles and haplotypes with HDL-C levels. Specific Aim 4. Genes/regions that are validated to be associated with high HDL-C in Aims 1-3 will be interrogated using publicly available phenotype and genome-wide genotype data from the Diabetes Genetics Initiative of Broad, Novartis, and Lund (Caucasian diabetics), the Framingham Heart Study (Caucasian), and the NHLBI CARE consortium (African-American) for association with HDL-C and related phenotypes. In addition, because subjects from the Framingham Heart Study and CARE have generally had a long period of follow-up observation, association of these genes/regions with cardiovascular outcomes will also be determined. We hypothesize that our GWA approach will serve to identify novel genes that cause or predispose to high HDL, generating new targets for HDL raising therapies. PUBLIC HEALTH RELEVANCE: We will perform a high density genome-wide SNP scan using the Illumina 550K chip. We hypothesize that our GWA approach will serve to identify novel genes that cause or predispose to high HDL, generating new targets for HDL raising therapies.