Abstract 5097: High Density SNP Association Analysis of Potential HDL Candidate Genes Reveals Molecular Architecture and Functionally Relevant Domains: Focus on CETP
Several genes are known to be associated with variation in human HDL-C levels, though in many cases the molecular architecture of these associations is not known. Basic research and mouse genetics have identified a large number of new genes that plausibly affect HDL metabolism but have not been associated with HDL-C levels in humans. GWAS has proven a powerful means to identify novel genes linked to complex phenotypes such as HDL-C. However, many genes are poorly represented on current arrays and correcting for a large number of tests can lead to rejecting marginally significant genes that are still important. We used a custom candidate gene array using tag-SNPs to extensively cover a large number of known and possible HDL candidate genes to interrogate a population of cases with extreme high HDL-C (>95th percentile; n=665) compared with low HDL-C (<25th percentile; n=703). The most significantly associated SNPs were in CETP (p<1×10−14). The array contains 100 CETP SNPs and the data reveals detailed association and LD in three discrete blocks. The figure⇓ below shows the association of CETP SNPs to HDL and indicates that the LD blocks have distinct properties regarding HDL association. In addition, the proximal LD block, which contains the most significant SNPs, is composed of two distinct LD sub-blocks which is apparent in the candidate gene array data (but not the HAPMAP). A better definition of the genetic architecture of CETP and its relationship to HDL-C will help resolve the relationship between CETP, HDL, and CAD. High-density candidate gene arrays will permit detailed interrogation and reveal insights of candidate genes that extend findings from genome-wide association studies.