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)和具体的挑战主题04-TW-101：“研究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。”未来几十年，全球2型糖尿病(T2 DM)疫情预计将恶化，尤其是在南亚，预计到2030年，南亚T2 DM患者人数将达到近1亿人。T2 DM是冠心病(CHD)的主要风险，在南亚，这种疾病的负担也在迅速增加。T2 DM与CHD风险增加之间的联系机制仍然知之甚少。有人提出，南亚人易患心脏代谢性疾病，这是由于遗传和生活方式因素共同促进了代谢功能障碍，但在南亚，直接证据很少。南亚从未对T2 DM与CHD之间的临床、流行病学、生化和遗传因素进行大规模、系统的研究。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调查提供了一个国际独一无二的机会，因为它已经：(1)招募了5000名确诊的心肌梗死(MI)患者和5000名对照，其中1850人患有T2 DM；(2)记录了广泛的临床和流行病学信息；以及(3)在10,000名参与者中完成了全基因组关联扫描。我们寻求支持在以下类别中分析一些可能与T2 DM和MI相关的生物标记物：(1)促动脉粥样硬化的载脂蛋白的血浆浓度和功能特性；(2)胆固醇反向运输的标记物；以及(3)与肥胖和胰岛素抵抗相关的标记物。我们将在10,000名参与者中分析大多数生物标记物，以便最大限度地评估他们与T2 DM和MI的关系。将对1850名T2 DM患者和2000名匹配的非T2 DM或MI的参与者进行检测，其中选定的生物标志物是特别需要劳动密集型的。有关这些新检测的代谢标志物的信息将与现有的PROMIS数据库合并，PROMIS数据库包含数百个相关临床和流行病学特征的数据，以及150万个基因变异的信息。将进行一系列预先指定的统计分析，以收获这个表型和基因丰富的数据库。分析将：(1)确定南亚人中与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心肌梗死风险的相关性的大小，包括单独和组合，同时校正潜在的混杂因素和人内变异性；(3)估计有多少T2 DM-MI关系是由传统风险因素以及每个待评估的代谢生物标志物/途径解释的；(4)通过利用现有的10,000名参与者的全基因组数据，识别和评估这些代谢生物标志物的遗传决定因素；以及(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记物的生活方式决定因素(特别强调烟草消费、体力活动和脂肪消费)。利用现有资源以及打折或捐赠的试剂盒将提供相当大的附加值。该项目将产生有关巴基斯坦T2 DM和CHD之间联系的新数据，从而促进科学理解，并为制定南亚地区预防和控制T2 DM和CHD的区域适当战略提供信息。我们将在巴基斯坦心肌梗死风险研究(PROIS)中进行与糖尿病、脂代谢和冠心病相关的检测。该项目将产生有关巴基斯坦T2 DM和CHD之间联系的新数据，从而促进科学理解，并为制定南亚地区预防和控制T2 DM和CHD的区域适当战略提供信息。

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.