Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates high-density lipoprotein cholesterol levels

Abstract

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.

Figure 1. SNP locations in the PCSK5 gene

Schematic representation of the human PCSK5 gene locus showing the exon structure and the location of the 19 polymorphisms (bottom panel) discovered through sequencing and the 9 genetic variants associated with HDL-C (upper panel) identified by genotyping. SNPs in bold are associated with HDL-C with P<0.01. Locations are based on RefSeq NM_006200.3.

Figure 2. LD map of SNPs investigated in the PCSK5 gene

The LD map was generated using Haploview. Numbers and white to black shading indicate r² values (black=high, white=low).

Figure 3. Conceptual model of PCSK5 variants’ effect.

Genetic variation at PCSK5, resulting in complete or partial PC5/6 loss of function, may be responsible for the inability of PC5/6 to activate ANGPLT3 or directly inactivate EL. This will overexpress EL, increasing phospholipase activity on HDL particles, resulting in smaller HDL with decreased cholesterol content.