A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis

J Am Coll Cardiol. 2005 May 17;45(10):1611-9. doi: 10.1016/j.jacc.2005.01.051. Epub 2005 Apr 21.

Abstract

Objectives: We sought to determine the effects of PCSK9 variants on plasma low-density lipoprotein cholesterol (LDL-C) levels, severity of coronary atherosclerosis, and response to statin therapy in the Lipoprotein Coronary Atherosclerosis Study (LCAS) population.

Background: Mutations in PCSK9 cause autosomal-dominant hypercholesterolemia. We hypothesized that PCSK9 variants could affect plasma LDL-C in individuals with polygenic hypercholesterolemia.

Methods: We sequenced all 12 exons and boundaries to detect novel polymorphisms, and genotyped 372 subjects in LCAS and 319 subjects in a second independent population for six polymorphisms, including novel leucine repeats, by fluorescently tagged markers. We reconstructed haplotypes using a Bayesian algorithm.

Results: Permutation test results showed statistically significant differences in global haplotype distribution among the tertiles of LDL-C (odds ratio [OR]: 2.36, 95% confidence interval [CI]: 1.90 to 4.32, p = 0.005) and minimum lumen diameter of coronary lesions (OR: 1.83, 95% CI: 1.01 to 3.55, p = 0.045). Regression analysis identified haplotype 3 as an independent determinant of LDL-C levels (adjusted R2 = 2.2%, F = 9.37, p = 0.002). Haplotype structure analysis identified E670G as the determinant variant, exerting a dose effect (GG > EG > EE) and accounting for 3.5% of plasma LDL-C variability (F = 14.6, p < 0.001). Plasma total cholesterol, apolipoprotein B, and lipoprotein (a) levels were also associated with the E670G variant. Distributions of the E670G genotypes in an independent normolipidemic and the hyperlipidemic LCAS populations were significantly different (F = 7.2, p = 0.027). No significant treatment-by-genotype interactions were detected. The false positive report probability was between 2% and 8%.

Conclusions: Haplotype 3 encompassing the E670G variant is an independent determinant of plasma LDL-C levels and the severity of coronary atherosclerosis.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Anticholesteremic Agents / therapeutic use
  • Cholesterol / blood
  • Cholesterol, HDL / blood
  • Chromosome Aberrations
  • Coronary Artery Disease / diagnosis
  • Coronary Artery Disease / drug therapy
  • Coronary Artery Disease / genetics*
  • DNA Mutational Analysis
  • Fatty Acids, Monounsaturated / therapeutic use
  • Female
  • Fluvastatin
  • Gene Frequency / genetics
  • Genes, Dominant
  • Genetic Markers / genetics*
  • Genetic Variation / genetics*
  • Genotype
  • Haplotypes*
  • Humans
  • Hyperlipoproteinemia Type II / drug therapy
  • Hyperlipoproteinemia Type II / genetics*
  • Indoles / therapeutic use
  • Lipoprotein(a) / blood
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide / genetics*
  • Predictive Value of Tests
  • Prognosis
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases / genetics*
  • Treatment Outcome
  • Triglycerides / blood

Substances

  • Anticholesteremic Agents
  • Cholesterol, HDL
  • Fatty Acids, Monounsaturated
  • Genetic Markers
  • Indoles
  • Lipoprotein(a)
  • Triglycerides
  • Fluvastatin
  • Cholesterol
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases