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）： 基于GWAS的基础的下一步。“全面的生物标志物研究旨在利用10K南亚人的现有GWAS的NHLBI NHLBI全基因组协会研究（GWAS）的NHLBI投资组合（GWAS）很大，但目前不包括南亚人，即使是冠心病的负担（CHD）（CHD）在南亚人（CHD）中，较高的是IS高的人（CHD）（占较高的人）和100万人的居民和100万人的居住地。南亚人的研究是一个战略优先事项，既是科学发现，与其他种族和族裔群体进行比较，并且为了疾病控制的目的，这一宏伟的机会都可以利用NHLBI利用了现有的大型南亚心肌梗塞（MI）病例对照研究的机会。进入NHLBI GWAS投资组合。 （2）记录了数百个临床和生活方式特征； （3）在10,000名参与者中完成了全基因组的关联扫描（Illumina 660k Quad）（并在4000名参与者中分析了IBC 50K“ Cardiochip”基因阵列）和（4）（4）分析了标准脂质，葡萄糖和HBA1C。我们寻求支持通过测定与动脉粥样硬化，斑块破裂和/或血栓形成可能相关的血浆生物标志物，从而为Promis增加全面的生化维度。为了促进与南亚样本的比较，我们将分析先前在其他种族的GWA中进行研究的分析物，包括现有的NHLBI队列。为了研究与南亚人特别相关的标记，我们还将分析以前GWAS中没有报道的一些新型分析物。 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）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，半胱氨酸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，SICAM-1，血清淀粉样蛋白A，MMP-9，E-选择蛋白，P-塞链蛋白，P-链球菌，CD40 CD40 CD40 Gibrinogen，Fibrinogen，Fibinogen，Von Willebrand dimer和Dimer和Dimer和Dimer和Dimer）。该提案将提高对南亚MI的病因途径的了解，并将扩大针对心血管风险和疾病的遗传基础的NHLBI GWAS研究范围。 公共卫生相关性声明： 遗传关联研究的NHLBI投资组合目前不包括对南亚人进行的大型，良好的研究，尽管南亚人的冠状动脉疾病负担（CHD）很高且迅速增加。我们建议巴基斯坦的心肌梗塞研究风险（Promis）将是NHLBI GWAS投资组合的高度成本效益。我们通过测定与动脉粥样硬化，斑块破裂和/或血栓形成可能相关的血浆生物标志物来寻求对Promis的其他血液标记。