title: Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population.
abstract: Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low-density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucleotide polymorphisms (SNPs), R46L and E670G, in 5783 elderly participants in Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), of whom 43% had a history of vascular disease at baseline, and who were randomized to pravastatin or placebo with followup. In this population 3.5% were carriers of the T allele at R46L, and these subjects had significantly (p<0.001) lower levels of LDL C (mean, -10%), no difference in LDL C lowering response to pravastatin, and a non-significant 19% unadjusted and 9% adjusted decreased risk of vascular disease at baseline, with no on trial effect. Moreover, 6.0% were carriers of the G allele at E670G with no significant relationships with baseline LDL C, response to pravastatin, or vascular disease risk being observed. Our data support the concept that the rare allele of the R46L SNP at the PCSK9 locus significantly lowers LDL C, but does not greatly reduce CHD risk in an elderly population with a high prevalence of cardiovascular disease.
authors.affiliation: Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
authors.forename: Eliana
authors.initials: E
authors.lastname: Polisecki
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.forename: Michele
authors.initials: M
authors.lastname: Robertson
authors.forename: Alex D
authors.initials: AD
authors.lastname: McMahon
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: Christopher
authors.initials: C
authors.lastname: Packard
authors.forename: James
authors.initials: J
authors.lastname: Shepherd
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Blauw
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.forename: Michael B
authors.initials: MB
authors.lastname: Murphy
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D008078:Cholesterol, LDL / Q000187:drug effects / Q000235:genetics*; D003327:Coronary Disease / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D015810:Linkage Disequilibrium; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017035:Pravastatin / Q000235:genetics / Q000494:pharmacology; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D017035:Pravastatin