A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol

Ingrid K. Kotowski, Alexander Pertsemlidis, Amy Luke, Richard S. Cooper, Gloria L. Vega, Jonathan C. Cohen, Helen H. Hobbs

Research output: Contribution to journalArticlepeer-review

465 Scopus citations


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 (<5 th percentile) and highest (>95 th 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.

Original languageEnglish (US)
Pages (from-to)410-422
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - Mar 2006
Externally publishedYes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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