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.