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

描述（由申请人提供）：本申请涉及广泛的挑战领域（04）和特定的挑战主题04-TW-101：“检查低收入和中等收入国家糖尿病和心血管疾病之间的临床和机制联系。“全球2型糖尿病（T2 DM）的流行预计将在未来几十年内恶化，特别是在南亚，预计到2030年T2 DM患者人数将达到近1亿。T2 DM是冠心病（CHD）的主要风险，其负担在南亚也迅速增加。T2 DM与CHD风险增加相关的机制仍知之甚少。有人提出，由于遗传和生活方式因素的结合，促进代谢功能障碍，南亚人易患心脏代谢疾病，但南亚的直接证据很少。在南亚地区，从未进行过将T2 DM与CHD联系起来的临床、流行病学、生化和遗传因素的大规模系统研究。巴基斯坦心肌梗死风险研究（PROMIS）为以快速、可靠和具有成本效益的方式进行此类研究提供了国际上独一无二的机会，因为它已经：（1）招募了5000例心肌梗死（MI）确诊病例和5000例对照，其中1850例患有T2 DM;（2）记录了广泛的临床和流行病学信息;（3）在10，000名参与者中完成了全基因组关联扫描。我们寻求支持，以测定以下类别中可能将T2 DM和MI联系起来的许多生物标志物：（1）血浆浓度以及含促动脉粥样硬化载脂蛋白B的脂蛋白的功能特性;（2）胆固醇逆向转运的标志物;和（3）与肥胖和胰岛素抵抗相关的标志物。我们将在10，000名参与者中分析大多数生物标志物，以最大限度地评估其与T2 DM和MI的关系。将在1850例T2 DM患者和2000例匹配的无T2 DM或MI的受试者中测量所选的生物标志物，这些生物标志物的测定尤其需要大量劳动力。关于这些新测定的代谢标志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> 150万个遗传变异的信息。将进行一系列预先指定的统计分析，以收集该表型和基因型丰富的数据库。分析将：（1）确定与南亚人T2 DM最密切相关的代谢生物标志物;（2）估计这些生物标志物与MI风险的关联程度，包括单独和组合，同时校正潜在的混杂因素和个体内变异性;（3）估计T2 DM-MI关系中有多少是由常规风险因素以及每种代谢生物标志物解释的。（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;以及（5）识别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、体育活动和脂肪消费），000名参与者。通过利用现有资源以及折扣或捐赠的化验包，将提供相当大的附加值。该项目将产生关于巴基斯坦2型糖尿病和冠心病之间联系的新数据，从而促进科学认识，并为制定适合南亚地区的预防和控制2型糖尿病和冠心病的战略提供信息。我们将在巴基斯坦心肌梗死风险研究（PROMIS）中进行与糖尿病、脂质代谢和冠状动脉疾病相关的检测。该项目将产生关于巴基斯坦2型糖尿病和冠心病之间联系的新数据，从而促进科学认识，并为制定适合南亚地区的预防和控制2型糖尿病和冠心病的战略提供信息。

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.