A low level of high density lipoprotein cholesterol (HDL-C) is an independent risk factor for coronary heart disease (CHD). It is estimated that more than 50% of the variation in HDL-C levels in humans is genetically determined. There is great interest in the concept that common genetic variants contribute to inherited differences in the susceptibility to common diseases. One promising approach to address this issue is to relate variation in DNA sequence with patient characteristics in population-based association studies. We are proposing to identify allelic variants associated with the low HDL trait, using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT, cases), a study designed to explore the benefits of HDL-raising with gemfibrozil in men having low HDL-C (<40 mg/dL), normal LDL-C (<140 mg/dL) and known CHD, and the Framingham Offspring Study (FOS, controls). Our primary aims are to identify: 1) susceptibility loci for the low HDL trait, 2) allelic variants associated with levels of apolipoproteinA-l-containing HDL subspecies, and 3) allelic variants associated with response to gemfibrozil in VA-HIT. For Aim 1, we will examine biological (n=38) and positional (n=3) candidates. The former will include genes involved in HDL metabolism, insulin resistance and inflammation, while the latter will be selected on the basis of results from genome-wide linkage scans for quantitative trait loci associated with HDL-C levels in FOS. For each candidate, we will use HapMap data in order to select a maximally informative set of SNPs (tagSNPs), which will allow us to resolve >80% of all haplotypes. Based on this algorithm, we will genotype 1 SNP per 2500 bp across each candidate gene/region. To address the issue of population stratification, we will employ a structured association approach, using a set of 250 markers that has the ability to detect modest amounts of stratification. The results of this work will provide important insight into the contribution of allelic variation in the pathways of HDL metabolism, inflammation, and insulin resistance to the complex phenotype of low HDL-C.