Markers of the metabolic syndrome linking type 2 diabetes and MI in South Asia

南亚地区 2 型糖尿病和 MI 之间关联的代谢综合征标志物

• 批准号: 7937059
• 负责人: John Navid Danesh
• 金额: $ 50万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937059
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Apolipoproteins B; Apolipoproteins C; Area; Asia; Biochemical Genetics; Biological Assay; Biological Markers; Cardiovascular Diseases; Categories; Characteristics; Clinical; Consumption; Coronary heart disease; Country; Data; Databases; Development; Diabetes Mellitus; Enzymes; Epidemic; Epidemiology; Fatty acid glycerol esters; Functional disorder; Genetic Determinism; Harvest; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Income; Inherited; Insulin; Insulin Resistance; Investigation; Leptin; Life Style; Link; Lipoprotein (a); Lipoproteins; Measures; Metabolic; Metabolic Marker; Metabolic syndrome; Myocardial Infarction; Names; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pakistan; Participant; Pathway interactions; Patients; Peroxidases; Persons; Physical activity; Plasma; Property; Recruitment Activity; Renal function; Resources; Risk; Risk Factors; Scientific Advances and Accomplishments; Series; South Asian; Specific qualifier value; Tobacco use; United States National Institutes of Health; adiponectin; cost; discount; genetic variant; genome wide association study; genome-wide; lifestyle factors; lipid metabolism; lipoprotein-associated phospholipase A(2); liver function; novel; prevent; programs; reverse cholesterol transport

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) and specific Challenge Topic, 04-TW-101: "Examining the clinical and mechanistic link between diabetes mellitus and cardiovascular disease in low- and middle-income countries." The global epidemic of type 2 diabetes mellitus (T2DM) is expected to worsen over the coming decades, particularly in South Asia where the number of people with T2DM is projected to reach almost 100M by 2030. T2DM is a major risk for coronary heart disease (CHD), the burden of which is also rapidly increasing in South Asia. The mechanisms that link T2DM with increased risk of CHD remain poorly understood. It has been proposed that South Asians are predisposed to cardiometabolic conditions owing to a combination of hereditary and lifestyle factors that promote metabolic dysfunction, but direct evidence in South Asia is sparse. A large, systematic study of clinical, epidemiological, biochemical and genetic factors linking T2DM to CHD in South Asia has never been done. The Pakistan Risk of Myocardial Infarction Study (PROMIS) provides an internationally unique opportunity to conduct such investigations in a rapid, reliable and cost-effective manner because it has already: (1) recruited 5000 confirmed cases of myocardial infarction (MI) and 5000 controls, of whom 1850 have T2DM; (2) recorded extensive clinical and epidemiological information; and (3) completed a genome-wide association scan in 10,000 participants. We seek support to assay a number of biomarkers that may link T2DM and MI in the following categories: (1) plasma concentrations as well as functional properties of pro- atherogenic apoB-containing lipoproteins; (2) markers of reverse cholesterol transport; and (3) markers related to adiposity and insulin resistance. We will assay the majority of the biomarkers in 10,000 participants in order to maximize power to assess their relationships to both T2DM and MI. Selected biomarkers which are especially labor intensive to assay will be measured in 1850 patients with T2DM and 2000 matched participants without T2DM or MI. Information on such newly-assayed metabolic markers will be merged with the existing PROMIS database, which contains data on several hundred relevant clinical and epidemiological characteristics and information on >1.5M genetic variants. A series of pre-specified statistical analyses will be done to harvest this phenotypically- and genotypically- rich database. Analyses will: (1) identify the metabolic biomarkers most strongly associated with T2DM in South Asians; (2) estimate the magnitude of the associations of such biomarkers with MI risk, both singly and in combination, while correcting for potential confounding factors and within-person variability; (3) estimate how much of the T2DM-MI relationship is explained by conventional risk factors as well as each of the metabolic biomarkers/pathways to be assessed; (4) identify and evaluate the genetic determinants of these metabolic biomarkers by exploiting existing genome-wide data in 10,000 participants; and (5) identify and evaluate the lifestyle determinants of these metabolic markers (with particular emphasis on tobacco consumption, physical activity and fat consumption) by exploiting existing clinical and epidemiological data on 10,000 participants. Considerable added value will be provided by the utilization of existing resources as well as discounted or donated assay kits. This project will generate novel data regarding the links between T2DM and CHD in Pakistan, thereby advancing scientific understanding and informing the development of regionally appropriate strategies to prevent and control T2DM and CHD in South Asia. We will perform assay related to diabetes, lipid metabolism and coronary disease in the Pakistan Risk of Myocardial Infarction Study (PROMIS). This project will generate novel data regarding the links between T2DM and CHD in Pakistan, thereby advancing scientific understanding and informing the development of regionally appropriate strategies to prevent and control T2DM and CHD in South Asia.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (04) 和具体的挑战主题 04-TW-101：“检查低收入和中等收入国家糖尿病与心血管疾病之间的临床和机制联系。”预计未来几十年，2 型糖尿病 (T2DM) 的全球流行将进一步恶化，特别是在南亚，预计到 2030 年，该地区 T2DM 患者人数将达到近 1 亿。T2DM 是冠心病 (CHD) 的主要风险，南亚的冠心病负担也在迅速增加。 T2DM 与冠心病风险增加之间的联系机制仍知之甚少。有人提出，由于遗传和生活方式因素共同促进代谢功能障碍，南亚人容易患心脏代谢疾病，但南亚的直接证据很少。南亚地区尚未对 T2DM 与 CHD 相关的临床、流行病学、生化和遗传因素进行过大规模、系统的研究。巴基斯坦心肌梗死风险研究 (PROMIS) 提供了一个国际上独特的机会，以快速、可靠和具有成本效益的方式开展此类调查，因为它已经： (1) 招募了 5000 名心肌梗死 (MI) 确诊病例和 5000 名对照者，其中 1850 名患有 T2DM； (2)记录了大量的临床和流行病学信息； (3) 完成了 10,000 名参与者的全基因组关联扫描。我们寻求支持来分析一些可能在以下类别中将 T2DM 和 MI 联系起来的生物标志物：(1) 血浆浓度以及促动脉粥样硬化的含 apoB 脂蛋白的功能特性； (2)胆固醇逆向转运标志物； (3)与肥胖和胰岛素抵抗相关的标志物。我们将检测 10,000 名参与者的大多数生物标志物，以便最大限度地评估他们与 T2DM 和 MI 的关系。将在 1850 名 T2DM 患者和 2000 名没有 T2DM 或 MI 的匹配参与者中测量特别需要大量劳动的选定生物标志物。有关此类新测定的代谢标记物的信息将与现有的 PROMIS 数据库合并，该数据库包含数百个相关临床和流行病学特征的数据以及 > 1.5M 遗传变异的信息。将进行一系列预先指定的统计分析来收获这个表型和基因型丰富的数据库。分析将：(1) 确定与南亚人 T2DM 最密切相关的代谢生物标志物； (2) 估计这些生物标志物与心肌梗死风险的关联程度，无论是单独的还是组合的，同时纠正潜在的混杂因素和人体内的变异性； (3) 估计 T2DM-MI 关系在多大程度上可以通过传统危险因素以及待评估的每个代谢生物标志物/途径来解释； (4) 通过利用 10,000 名参与者的现有全基因组数据来识别和评估这些代谢生物标志物的遗传决定因素； (5) 通过利用 10,000 名参与者的现有临床和流行病学数据，确定和评估这些代谢标志物的生活方式决定因素（特别强调烟草消费、体力活动和脂肪消耗）。利用现有资源以及折扣或捐赠的检测试剂盒将提供相当大的附加值。该项目将生成有关巴基斯坦 T2DM 和 CHD 之间联系的新数据，从而促进科学认识并为制定适合区域的战略以预防和控制南亚的 T2DM 和 CHD 提供信息。我们将在巴基斯坦心肌梗死风险研究 (PROMIS) 中进行与糖尿病、脂质代谢和冠心病相关的检测。该项目将生成有关巴基斯坦 T2DM 和 CHD 之间联系的新数据，从而促进科学认识并为制定适合区域的战略以预防和控制南亚的 T2DM 和 CHD 提供信息。