|
|
||||||||||
|
J Am Coll Cardiol, 2005; 45:1611-1619, doi:10.1016/j.jacc.2005.01.051 © 2005 by the American College of Cardiology Foundation |


* 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.
| |||||||||||||||||
Related articles in JACC:
This article has been cited by other articles:
![]() |
K. E. North, H. H. H. Goring, S. A. Cole, V. P. Diego, L. Almasy, S. Laston, T. Cantu, B. V. Howard, E. T. Lee, L. G. Best, et al. Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study J. Lipid Res., January 1, 2006; 47(1): 59 - 66. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. J.P. Kastelein, S. W. Fouchier, and J. C. Defesche What Promise Does PCSK9 Hold? J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1620 - 1621. [Full Text] [PDF] |
||||
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |