title: 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.
  
  
  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.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Laboratories, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: Iulia
authors.initials: I
authors.lastname: Iatan
authors.forename: Zari
authors.initials: Z
authors.lastname: Dastani
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ruel
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Lee
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vazquez
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D045702:Proprotein Convertase 5 / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D045702:Proprotein Convertase 5