Comprehensive biomarker study to capitalize on existing GWAS in 10K South Asians

描述（由申请人提供）： 基因发现的下一步：建立在GWAS基础上。NHLBI的全基因组关联研究（GWAS）组合很大，但目前不包括南亚人，尽管南亚人（包括约100万生活在美国的人和全球15亿人）的冠心病（CHD）负担很高且迅速增加。对南亚人进行研究是一项战略优先事项，无论是为了科学发现，与其他种族和族裔群体进行比较，还是为了疾病控制。这项重大机遇提案为NHLBI提供了利用现有大型南亚心肌梗死（MI）病例对照研究的机会，该研究中受试者已经进行了全基因组基因分型。通过资助额外的生物标志物研究，NHLBI可以将这项独特的研究纳入NHLBI GWAS组合。巴基斯坦心肌梗死风险研究（PROMIS）在国际上是独一无二的，因为在南亚人群中，它已经：（1）招募了>5000例急性心肌梗死（MI）确诊病例和>5000例对照（目标是到2009年底10，000例病例和10，000例对照）;（2）记录数百个临床和生活方式特征;（3）在10，000名参与者中完成全基因组关联扫描（Illumina 660 K Quad）（并在4000名参与者中测定IBC 50 K“心脏芯片”基因阵列）和（4）测定标准脂质、葡萄糖和HbA 1c。我们寻求支持，以增加一个全面的生化层面PROMIS通过分析血浆生物标志物可能相关的动脉粥样硬化，斑块破裂和/或血栓形成。为了便于与我们的南亚样本进行比较，我们将分析先前在其他种族群体的GWAS中研究的分析物，包括现有的NHLBI队列。为了研究与南亚人特别相关的标志物，我们还将检测一些以前在GWAS中没有报道的新分析物。我们将检测以下标志物：（1）脂质和脂蛋白（apoA-I、apoA-II、apoB、apoC-III、apoE、脂蛋白（a）、脂蛋白亚类、氧化磷脂、oxLDL自身抗体、LpPLA 2、sPLA 2、髓过氧化物酶）;（2）胰岛素抵抗和肥胖（胰岛素、C肽、脂联素、瘦素、β-内酰胺酶、肝功能酶）;（3）肾功能（肌酸酐、胱抑素C、ADMA、尿酸、25（OH）维生素D、甲状旁腺激素）;（4）炎症与止血（hsCRP、MCP-1、IL-6、sTNFRII、sVCAM-1、sICAM-1、血清淀粉样蛋白A、MMP-9、E-选择素、P-选择素、CD 40配体、纤维蛋白原、血管性血友病因子和D-二聚体）。该提案将促进对南亚人MI病因学途径的理解，并将扩大NHLBI GWAS研究的范围，重点关注心血管风险和疾病的遗传基础。 公共卫生相关性声明： NHLBI的遗传关联研究组合目前不包括南亚人的大规模、特征良好的研究，尽管南亚人的冠心病（CHD）负担很高且迅速增加。我们建议巴基斯坦心肌梗死风险研究（PROMIS）将是NHLBI GWAS投资组合中极具成本效益的补充。我们通过分析与动脉粥样硬化形成、斑块破裂和/或血栓形成潜在相关的血浆生物标志物，寻求对PROMIS的额外血液标志物的支持。

DESCRIPTION (provided by applicant): Next Steps in Gene Discovery: Building upon GWAS." Comprehensive biomarker study to capitalize on existing GWAS in 10K South Asians The NHLBI portfolio of genome-wide association studies (GWAS) is large but does not currently include South Asians, even though the burden of coronary heart disease (CHD) among South Asians (who comprise ~1 million people living in the US and 1.5 billion worldwide) is high and rapidly increasing. Conduct of studies in South Asians is a strategic priority, both for scientific discovery, for comparison with other racial and ethnic groups, and for disease control purposes. This Grand Opportunity proposal provides the NHLBI with the opportunity to capitalize on an existing large South Asian myocardial infarction (MI) case-control study in which subjects have already been genome-wide genotyped. By funding additional biomarker studies, NHLBI can bring this unique study into the NHLBI GWAS portfolio. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is internationally unique because in a South Asian population it has already: (1) recruited >5000 confirmed cases of acute myocardial infarction (MI) and >5000 controls (goal is 10,000 cases and 10,000 controls by end of 2009); (2) recorded several hundred clinical and lifestyle characteristics; (3) completed a genome-wide association scan (Illumina 660K Quad) in 10,000 participants (and assayed the IBC 50K "cardiochip" gene array in 4000 participants) and (4) assayed standard lipids, glucose and HbA1c. We seek support to add a comprehensive biochemical dimension to PROMIS by assaying plasma biomarkers potentially relevant to atherogenesis, plaque rupture and/or thrombosis. To facilitate comparisons with our South Asian sample, we will assay analytes previously studied in GWAS of other ethnic groups, including in the existing NHLBI cohorts. To study markers of particular relevance to South Asians, we will also assay some novel analytes not previously reported in previous GWAS. We will assay markers of: (1) lipids and lipoproteins (apoA-I, apoA-II, apoB, apoC-III, apoE, lipoprotein(a), lipoprotein subclasses, oxidized phospholipids, authoantibodies to oxLDL, LpPLA2, sPLA2, myeloperoxidase); (2) insulin resistance and adiposity (insulin, C-peptide, adiponectin, leptin, resistin, liver function enzymes); (3) renal function (creatinine, cystatin C, ADMA, uric acid, 25(OH)vitamin D, parathyroid hormone); and (4) inflammation and hemostasis (hsCRP, MCP-1, IL-6, sTNFRII, sVCAM-1, sICAM-1, serum amyloid A, MMP-9, E-selectin, P-selectin, CD40 ligand, fibrinogen, von Willebrand factor, and D-dimer). This proposal will advance understanding of etiological pathways for MI in South Asians and will expand the scope of NHLBI GWAS studies focused on the genetic basis of cardiovascular risk and disease. Public Health Relevance Statement: The NHLBI portfolio of genetic association studies does not currently include a large, wellcharacterized study of South Asians, even though the burden of coronary heart disease (CHD) among South Asians is high and rapidly increasing. We propose that the the Pakistan Risk of Myocardial Infarction Study (PROMIS) will be a highly cost-effective addition to the NHLBI GWAS portfolio. We seek support for additional blood markers to PROMIS by assaying plasma biomarkers potentially relevant to atherogenesis, plaque rupture and/or thrombosis.