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）：此申请解决了广泛的挑战领域（04）和特定的挑战主题，04-TW-101：“研究低收入国家和中等收入国家的糖尿病和心血管疾病之间的临床和机械联系。”预计在未来几十年中，预计2型糖尿病（T2DM）的全球流行病将恶化，尤其是在南亚，预计到2030年，T2DM的T2DM人数预计将近100m。T2DM是冠心病（CHD）的主要风险（CHD），南西亚的负担也很快增加。将T2DM与CHD风险增加的机制保持不足。有人提出，由于遗传性和生活方式因素的结合，南亚人倾向于心脏代谢条件，这些因素促进了代谢功能障碍，但南亚的直接证据很少。一项针对南亚T2DM与CHD联系的临床，流行病学，生化和遗传因素的大型系统研究从未进行过。巴基斯坦的心肌梗塞研究风险（PROMIS）提供了一个国际独特的机会，以快速，可靠和成本效益的方式进行此类调查，因为它已经具有：（1）招募5000例确认的心肌梗塞（MI）和5000个对照案件，其中1850个具有T2DM； （2）记录了广泛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协会扫描。我们寻求支持分析可能将T2DM和MI连接到以下类别中的许多生物标志物：（1）血浆浓度以及含有动脉粥样硬化APOB的脂蛋白的功能特性； （2）反向胆固醇运输的标记； （3）与肥胖和胰岛素抵抗有关的标记。我们将在10,000名参与者中分析大多数生物标志物，以最大程度地评估其与T2DM和MI的关系。在1850名T2DM和2000名没有T2DM或MI的参与者的患者中，将测量尤其是劳动力大量分析的精选生物标志物。有关此类新代谢标记的信息将与现有的Promis数据库合并，该数据库包含有关数百个相关临床和流行病学特征的数据，以及有关> 150万个遗传变异的数据。将进行一系列预先指定的统计分析，以收集表型和基因型富含数据库。分析将：（1）确定南亚人与T2DM最密切相关的代谢生物标志物； （2）估计此类生物标志物与MI风险的关联的大小，无论是单独还是组合，同时纠正了潜在的混杂因素和人内的可变性； （3）估算了传统的风险因素以及要评估的每种代谢生物标志物/途径的估计，T2DM-MI关系中有多少； （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）通过利用对10,000名参与者的现有临床和流行病学数据来确定和评估这些代谢标记的生活方式决定因素（特别强调烟草消费，体育活动和脂肪消耗）。利用现有资源以及折现或捐赠的测定套件将提供可观的附加值。该项目将生成有关巴基斯坦T2DM和CHD之间联系的新颖数据，从而促进了科学理解并告知了在南亚预防和控制T2DM和CHD的地区适当策略的发展。我们将进行与糖尿病，脂质代谢和冠状动脉疾病有关的测定法，这是巴基斯坦的心肌梗塞研究风险（Promis）。该项目将生成有关巴基斯坦T2DM和CHD之间联系的新颖数据，从而促进了科学理解并告知了在南亚预防和控制T2DM和CHD的地区适当策略的发展。