title: A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.
abstract: Selected missense mutations in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) cause autosomal dominant hypercholesterolemia, whereas nonsense mutations in the same gene are associated with low plasma levels of low-density lipoprotein cholesterol (LDL-C). Here, DNA sequencing and chip-based oligonucleotide hybridization were used to determine whether other sequence variations in PCSK9 contribute to differences in LDL-C levels. The coding regions of PCSK9 were sequenced in the blacks and whites from the Dallas Heart Study (n=3,543) who had the lowest (<5th percentile) and highest (>95th percentile) plasma levels of LDL-C. Of the 17 missense variants identified, 3 (R46L, L253F, and A443T) were significantly and reproducibly associated with lower plasma levels of LDL-C (reductions ranging from 3.5% to 30%). None of the low-LDL-C variants were associated with increased hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy. This finding is most consistent with the reduction in LDL-C being caused primarily by accelerating LDL clearance, rather than by reduced lipoprotein production. Association studies with 93 noncoding single-nucleotide polymorphisms (SNPs) at the PCSK9 locus identified 3 SNPs associated with modest differences in plasma LDL-C levels. Thus, a spectrum of sequence variations ranging in frequency (from 0.2% to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contribute to interindividual differences in LDL-C levels. These findings reveal that PCSK9 activity is a major determinant of plasma levels of LDL-C in humans and make it an attractive therapeutic target for LDL-C lowering.
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, 75390-9046, USA.
authors.forename: Ingrid K
authors.initials: IK
authors.lastname: Kotowski
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
authors.forename: Amy
authors.initials: A
authors.lastname: Luke
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.forename: Gloria L
authors.initials: GL
authors.lastname: Vega
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D008078:Cholesterol, LDL / Q000097:blood*; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases