Abstract 5526: Genetic Variation at PCSK5 Influences HDL-C Levels

Abstract

Low plasma HDL-C is a well-established risk factor for coronary artery disease. The role of endothelial lipase (EL) in HDL metabolism has been recently characterized. The proprotein convertase subtilisin/kexin 5 (PC5/6 or PCSK5) is known to inactivate both EL and lipoprotein lipase (LPL) ex vivo , enzymes critical in modulating plasma levels of HDL-C. In the present study, we investigated the role of human PCSK5 genetic variants on HDL-C; in addition, we characterized lipoprotein fractions in Pcsk5 +/− mice, compared with wild type. Sequencing of the PCSK5 gene was performed in 12 probands with low HDL-C (<5 th percentile) and 7 novel non-coding genetic variants were found. We genotyped these SNPs along with 163 tag SNPs and 12 additional SNPs (n=182 total) selected from the HapMap Project, in 457 individuals with documented coronary artery disease. We identified 10 SNPs associated with HDL-C (p<0.05), with the strongest result being rs11144782 (minor allele frequency: 0.164, p=0.002). In an analysis of HDL-C as a dichotomous trait, 3 of the 10 SNPs were also associated with low HDL-C at either the 5 th or the 10 th percentile (p<0.05). The rare allele of rs111447782 decreased HDL by 0.076 mmol/L in a gene dosage-dependent fashion. We further investigated the effect of this SNP on other lipoprotein levels and identified an association with very low density lipoprotein (p=0.039), triglycerides (p=0.049) and total ApoB (p=0.022) levels. Furthermore, in conditional regression analysis, we identified 3 additional SNPs contributing to HDL-C (p<0.05), all independent of the effect of rs11144782. In addition, we characterized serum from Pcsk5 KO mice. Serum from Pcsk5 +/− mice ( Pcsk5 −/− is embryonic lethal) showed reduction in HDL-C by gel permeation chromatography on HPLC and size redistribution of HDL species by 1D and 2D PAGGE. These results, and the rs11144782 SNP result presented above, are consistent with the concept that PCSK5 modulates HDL, likely upstream of EL and LPL. We conclude that variability at the PCSK5 gene locus influences HDL-C levels and consequently, atherosclerotic cardiovascular disease risk.