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.
OBJECTIVE
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.
Chen
Suet N
SN
Section of Cardiology, Center for Preventive Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Ballantyne
Christie M
CM
Gotto
Antonio M
AM
Tan
Yanli
Y
Willerson
James T
JT
Marian
Ali J
AJ
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D002869:Chromosome Aberrations; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D004252:DNA Mutational Analysis; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use; D005260:Female; D000077340:Fluvastatin; D005787:Gene Frequency / Q000235:genetics; D005799:Genes, Dominant; D005819:Genetic Markers / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000235:genetics*; D007211:Indoles / Q000627:therapeutic use; D017270:Lipoprotein(a) / Q000097:blood; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics*; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D005229:Fatty Acids, Monounsaturated; D005819:Genetic Markers; D007211:Indoles; D017270:Lipoprotein(a); D014280:Triglycerides; D000077340:Fluvastatin; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases