Published online before print August 22, 2009, doi: 10.1161/CIRCGENETICS.109.877811
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Original Articles |
Genetic Variation at the Proprotein Convertase Subtilisin/Kexin Type 5 Gene Modulates High-Density Lipoprotein Cholesterol Levels
From the Departments of Biochemistry (I.I., I.R., J.C.E., J.G.) and Human Genetics (Z.D., R.D., I.R., J.C.E., J.G.), Cardiovascular Research Laboratories, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montreal, Quebec, Canada; Department of Human Genetics (D.W.-V., J.C.L., A.H.-V., P.P.), David Geffen School of Medicine at UCLA, Los Angeles, Calif; Department of Medicine (M.-R.T.), Helsinki University Central Hospital, Helsinki, Finland; and Laboratory of Biochemical Neuroendocrinology (A.P., N.G.S.), Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Correspondence to Jacques Genest, MD, Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Ave W, Room M4/76, Montreal, Quebec, Canada H3A 1A1. E-mail jacques.genest{at}muhc.mcgill.ca
Received May 14, 2009; accepted June 23, 2009.
Background— A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. HDL particles are modulated by a variety of lipases, including endothelial lipase, a phospholipase present on vascular endothelial cells. The proprotein convertase subtilisin/kexin type 5 (PCSK5) gene product is known to directly inactivate endothelial lipase and indirectly cleave and activate angiopoetin-like protein 3, a natural inhibitor of endothelial lipase. We therefore investigated the effect of human PCSK5 genetic variants on plasma HDL-C levels.
Methods and Results— Haplotypes at the PCSK5 locus were examined in 9 multigenerational families that included 60 individuals with HDL-C <10th percentile. Segregation with low HDL-C in 1 family was found. Sequencing of the PCSK5 gene in 12 probands with HDL-C <5th percentile identified 7 novel variants. Using a 2-stage design, we first genotyped these single-nucleotide polymorphisms (SNPs) along with 163 tagSNPs and 12 additional SNPs (n=182 total) in 457 individuals with documented coronary artery disease. We identified 9 SNPs associated with HDL-C (P<0.05), with the strongest results for rs11144782 and rs11144766 (P=0.002 and P=0.005, respectively). The SNP rs11144782 was also associated with very low-density lipoprotein (P=0.039), triglycerides (P=0.049), and total apolipoprotein levels (P=0.022). In stage 2, we replicated the association of rs11144766 with HDL-C (P=0.014) in an independent sample of Finnish low HDL-C families. In a combined analysis of both stages (n=883), region-wide significance of rs11144766 and low HDL-C was observed (unadjusted P=1.86x10–4 and Bonferroni-adjusted P=0.031).
Conclusions— We conclude that variability at the PCSK5 locus influences HDL-C levels, possibly through the inactivation of endothelial lipase activity, and, consequently, atherosclerotic cardiovascular disease risk.
Key Words: cholesterol • coronary disease • genetics • lipids • lipoproteins