High-density genotyping and functional SNP localization in the CETP gene.

The cholesteryl ester transfer protein gene (CETP) has been the subject of hundreds of genetic analyses that typically focus on a small number of polymorphisms within a single ethnic group. Furthermore, the extent of DNA beyond the transcribed sequence from which single nucleotide polymorphisms (SNPs) may influence CETP expression has not been well defined. To better understand the role of natural variation in modulating CETP and high density lipoprotein-cholesterol (HDL-C) levels, dense genotyping of CETP and regions up to 15 kb on either side of the gene was carried out on >2,000 individuals. A complex, nonlinear set of linkage disequilibrium bins was found, with many bins interspersed along the DNA sequence and spread over large regions of the gene. Bins assigned based on large numbers of individuals matched the small subset of SNPs that had been assigned to bins previously with a small number of individuals. Associations of known functional SNPs with HDL-C were found, but there were suggestions that there are additional functional SNPs not characterized previously. Narrowing of the set of likely functional SNPs was accomplished by comparing associations observed in different ethnic groups. The promoter SNP most highly associated with HDL-C that is likely to be functional, position -4,502, alters a consensus transcription factor binding site.