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CLINICAL RESEARCH: ATHEROSCLEROSIS

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

Suet N. Chen, MS^_*, Christie M. Ballantyne, MD, FACC^_*, Antonio M. Gotto, Jr, MD, DPhil, FACC, Yanli Tan, RN^_*, James T. Willerson, MD, FACC and Ali J. Marian, MD, FACC^_*,_*

^_* Sections of Cardiology and Atherosclerosis, Center for Preventive Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas
Weill Medical College of Cornell University, New York, New York
University of Texas Health Science Center, Houston, Texas

Manuscript received October 14, 2004; revised manuscript received January 4, 2005, accepted January 11, 2005.

^_* Reprint requests and correspondence: Dr. Ali J. Marian, Baylor College of Medicine, Section of Cardiology, One Baylor Plaza, 519D, Houston, Texas 77030 (Email: amarian{at}bcm.tmc.edu).

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.

Abbreviations and Acronyms   ADH = autosomal-dominant hypercholesterolemia   FPRP = false positive report probability   HDL-C = high-density lipoprotein cholesterol   HWE = Hardy-Weinberg equilibrium   LCAS = Lipoprotein Coronary Atherosclerosis Study   LDL-C = low-density lipoprotein cholesterol   Lp(a) = lipoprotein (a)   MAF = minor allele frequencies   MI = myocardial infarction   PCR = polymerase chain reaction   PL-EM = partition-ligation-expectation-maximization   SNP = single nucleotide polymorphism   STR = short tandem repeat   TC = total cholesterol   TG = triglycerides

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