There is a strong inverse relationship between plasma levels of HDL-cholesterol (HDL-C) and the risk of coronary heart disease (CHD) that is independent of other known risk factors. In addition to environmental factors, genetics plays an important role in influencing plasma HDL-C levels and up to 76% of its variation is genetically determined. High heritability of HDL-C and its correlated lipid traits provide strong rationale to identify their genetic determinants, which may eventually lead to therapeutic treatments and/or prevention of CHD in the general population. Thus far, most of the efforts for identifying genes for HDL-C have been focused on screening a few selected single nucleotide polymorphisms (SNPs) per candidate gene. However, this approach is inadequate as it fails to cover the entire variation in a given gene and thus has given, for the most part, dismal results. The recent completion of the human genome project together with the comprehensive efforts by the International HapMap Project and other projects to provide dense marker map of each gene have provided the opportunity to thoroughly examine the role of biological candidate genes in relation to quantitative lipid traits. We will evaluate the role of genetic variation in 46 biological and positional candidate genes in relation to plasma HDL-C levels and correlated lipid and apolipoprotein levels in 804 African blacks from Nigeria and 691 U.S. whites. Because all proposed genes are biological candidates for HDL-C levels, a modest association with common tagSNPs (allele frequency 5% or greater) may imply that rare variants (allele frequency <5%) in these genes contribute to variation in HDL-C levels. Furthermore, those candidate genes which contain common variants may also contain rare variants that affect HDL levels. Therefore, we will resequence all candidate genes in individuals having extreme HDL-C levels (upper and lower fifth percentiles) to test the """"""""common trait - rare variant"""""""" hypothesis. In the second approach we will test the """"""""common trait - common variant"""""""" hypothesis by screening linkage disequilibrium (LD) -tagging SNPs and haplotypes. Those gene regions showing significant associations in the second approach will be subjected to in-depth molecular and statistical follow-up studies to find putative functional variants. As a result of these analyses, we should be able to definitively determine both rare and common variants that contribute to high and low HDL-C levels.
