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

利用现有 GWAS 对 10,000 南亚人进行全面的生物标志物研究

• 批准号: 7857425
• 负责人: John Navid Danesh
• 金额: $ 376.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7857425
• 关键词: Acute myocardial infarction; Age; Alleles; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Apolipoproteins B; Apolipoproteins C; Autoantibodies; Biochemical; Biochemical Pathway; Biological Assay; Biological Markers; Blood; C-Peptide; CCL2 gene; CD40 Ligand; CXCL12 gene; Case-Control Studies; Categories; Characteristics; Clinical; Complement Factor D; Consumption; Coronary; Coronary heart disease; Creatinine; Data; Dimensions; E-Selectin; Enzymes; Epidemiology; Ethnic Origin; Ethnic group; Fatty acid glycerol esters; Fibrin fragment D; Fibrinogen; Frequencies; Functional disorder; Funding; Gelatinase B; Genes; Genetic; Genetic Determinism; Genotype; Glucose; Glycosylated hemoglobin A; Goals; Hemostatic Agents; Hemostatic function; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interleukin-6; Kidney; Leptin; Life; Life Style; Lipids; Lipoprotein (a); Lipoproteins; Metabolic; Myocardial Infarction; N,N-dimethylarginine; National Heart, Lung, and Blood Institute; Obesity; P-Selectin; Pakistan; Parathyroid Hormones; Participant; Pathway interactions; Peroxidases; Persons; Phospholipids; Physical activity; Plasma; Population; Recruitment Activity; Renal function; Reporting; Research; Risk; Risk Factors; Rupture; Sampling; Series; Serum amyloid A protein; Smoking; South Asian; Testing; Thrombosis; Tobacco use; Uric Acid; Validation; Vitamin D; adiponectin; atherogenesis; base; cardiovascular disorder risk; case control; cohort; cost; disorder control; gene discovery; genetic association; genetic variant; genome wide association study; genome-wide; human PTH protein; kidney vascular structure; liver function; non-genetic; novel; post gamma-globulins; public health relevance; racial and ethnic; resistin; sex; von Willebrand Factor

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.

描述（由申请人提供）： 基因发现的后续步骤：以 GWAS 为基础。”利用 10K 南亚人现有 GWAS 的综合生物标志物研究 NHLBI 全基因组关联研究 (GWAS) 组合规模庞大，但目前不包括南亚人，尽管南亚人（大约有 100 万人生活在美国，全世界有 15 亿人）的冠心病 (CHD) 发病率很高，而且在南亚人中开展研究是一项战略重点，无论是对于科学界还是对于南亚人来说都是一项战略重点。这一重大机会提案为 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，其中受试者已经接受过研究。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 组合中，巴基斯坦心肌梗死风险研究 (PROMIS) 是国际上独一无二的，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年底招募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) 完成了 10,000 名参与者的全基因组关联扫描 (Illumina 660K Quad)（并分析了 4000 名参与者的 IBC 50K“cardiochip”基因阵列）和 (4) 分析了标准脂质、葡萄糖和 HbA1c。我们寻求支持，通过分析与动脉粥样硬化、斑块破裂和/或血栓形成潜在相关的血浆生物标志物，为 PROMIS 添加全面的生化维度。为了便于与我们的南亚样本进行比较，我们将分析之前在其他种族群体的 GWAS 中研究的分析物，包括现有的 NHLBI 队列中的分析物。为了研究与南亚人特别相关的标记物，我们还将分析一些以前在 GWAS 中未报道过的新分析物。我们将检测以下标记物：(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、LpPLA2、sPLA2、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、抵抗素、肝功能酶)； (3)肾功能(肌酐、胱抑素C、ADMA、尿酸、25(OH)维生素D、甲状旁腺激素)； (4)炎症和止血(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、CD40配体、纤维蛋白原、von血友病因子和 D-二聚体）。该提案将增进对南亚人 MI 病因学途径的了解，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。 公共卫生相关声明： 尽管南亚人的冠心病 (CHD) 负担很高且正在迅速增加，但 NHLBI 的遗传关联研究组合目前并不包括针对南亚人的大型、特征明确的研究。我们建议巴基斯坦心肌梗死风险研究 (PROMIS) 将成为 NHLBI GWAS 产品组合中极具成本效益的补充。我们通过分析可能与动脉粥样硬化、斑块破裂和/或血栓形成相关的血浆生物标志物，寻求对 PROMIS 的其他血液标志物的支持。