Published Online
on August 22, 2009

A more recent version of this article appeared on October 1, 2009

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Original Article

Genetic Variation at the Proprotein Convertase Subtilisin/Kexin Type 5 Gene Modulates HDL Cholesterol Levels

Iulia Iatan¹; Zari Dastani¹; Ron Do¹; Daphna Weissglas-Volkov²; Isabelle Ruel¹; Jenny C. Lee²; Adriana Huertas-Vazquez²; Marja-Riitta Taskinen³; Annik Prat⁴; Nabil G. Seidah⁴; Päivi Pajukanta²; James C. Engert¹ and Jacques Genest^1,5

¹ McGill University Health Centre & Royal Victoria Hospital, Montreal, Quebec, Canada;
² David Geffen School of Medicine at UCLA, Los Angeles, CA;
³ Helsinki University Central Hospital, Helsinki, Finland;
⁴ Clinical Research Institute of Montreal, Montreal, Quebec, Canada

^* Corresponding author; email: jacques.genest{at}muhc.mcgill.ca

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 (EL), a phospholipase present on vascular endothelial cells. The proprotein convertase subtilisin/kexin type 5 (PCSK5) is known to directly inactivate EL, and, indirectly, cleave and activate angiopoetin-like protein 3, a natural inhibitor of EL. 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 nine multi-generational families that included 60 individuals with HDL-C<10^th percentile. Segregation with low HDL-C in one family was found. Sequencing of the PCSK5 gene in 12 probands with HDL-C<5^th percentile identified seven novel variants. Using a two-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 nine 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 VLDL (P=0.039), TG (P=0.049) and total apoB 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 EL activity and consequently, atherosclerotic cardiovascular disease risk.

Key Words: cholesterol • coronary disease • genetics • lipids • lipoproteins