Genetics of Elevated High Density Lipoprotein Cholesterol

描述（由申请人提供）：已知“家族性高脂蛋白血症”综合征或高密度脂蛋白胆固醇（HDL-C）升高与长寿和预防动脉粥样硬化性心血管疾病有关。家族性高胆固醇脂蛋白血症的唯一已证实的分子病因是纯合子胆固醇酯转移蛋白（CETP）缺乏症，这几乎仅在日本发现，并导致了药理学CETP抑制作为提高HDL-C水平的策略的概念。我们招募了我们认为是现有最大的高HDL-C胆固醇水平的非日本先证者及其核心和大家族队列，以确定导致HDL-C升高的新遗传因素。我们将使用Illumina 550 K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HDL-C QTL。具体目标1。将使用Illumina HumanHap 550 BeadChip平台对750例具有极高HDL-C的高加索病例和1500例高加索对照（<第50百分位数）进行全基因组关联研究。将使用经典病例对照设计进行数据分析，以鉴定与极高HDL-C表型最强相关的SNP，并进行额外分析以评估与极高HDL-C水平相关的CNV。具体目标2。来自Aim 1中全基因组扫描的0.5-1%的最有希望的SNP以及捕获新的或显著的CNV的SNP将在500例病例（>第90百分位数）和1000例对照（<第50百分位数）的独立高加索病例对照组中进行基因分型，受试者来自护士健康和健康专业人员随访研究。HWE检测后，将检测SNP等位基因和基因型与病例对照状态的相关性。此外，将对目标1和目标2的病例和对照进行联合分析，并检验与HDL-C病例对照状态的相关性。具体目标3。将在一个独立的基于家族的队列（250个极高HDL-C先证者家族，包括高加索人和非洲裔美国人先证者/家族）和代表美国的基于人群的样本（NHANES III）（包括白人、非西班牙裔黑人和墨西哥裔美国人，n=7159）中，对基于目标1和2的约20个最有希望的基因/区域进行密集基因分型。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检验（FBAT）来检测HDL-C与SNP等位基因和单倍型的关联。在NHANES III队列中，将使用线性回归来测试SNP等位基因和单倍型与HDL-C水平之间的关联。具体目标4。将使用来自Broad、Novartis和隆德（高加索糖尿病）糖尿病遗传学倡议、Frachial Heart研究（高加索人）和NHLBI CARE联盟（非洲裔美国人）的公开可用表型和全基因组基因型数据，对目的1-3中经验证与高HDL-C相关的基因/区域进行质询，以确定与HDL-C和相关表型的相关性。此外，由于Frachial Heart研究和CARE的受试者通常有较长时间的随访观察，因此还将确定这些基因/区域与心血管结局的相关性。我们假设，我们的GWA方法将有助于识别导致或易患高HDL的新基因，为HDL升高疗法产生新的靶点。公共卫生相关性：我们将使用Illumina 550 K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HDL的新基因，为HDL升高疗法产生新的靶点。

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.