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CLINICAL RESEARCH: GENETICS AND CORONARY ARTERY DISEASE

Association of the Trp719Arg Polymorphism in Kinesin-Like Protein 6 With Myocardial Infarction and Coronary Heart Disease in 2 Prospective Trials

The CARE and WOSCOPS Trials

Olga A. Iakoubova, MD, PhD^_*,_*, Carmen H. Tong, BS^_*, Charles M. Rowland, MS^_*, Todd G. Kirchgessner, PhD, Bradford A. Young, PhD^_*, Andre R. Arellano, BS^_*, Dov Shiffman, PhD^_*, Marc S. Sabatine, MD, MPH, Hannia Campos, PhD, Christopher J. Packard, DSc^||, Marc A. Pfeffer, MD, PhD, Thomas J. White, PhD^_*, Eugene Braunwald, MD, FACC, James Shepherd, PhD^||, James J. Devlin, PhD^_* and Frank M. Sacks, MD^,

^_* Celera, Inc., Alameda, California
Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Harvard School of Public Health, Boston, Massachusetts
^|| University of Glasgow and Royal Infirmary, Glasgow, United Kingdom.

Manuscript received May 8, 2007; accepted May 23, 2007.

^_* Reprint requests and correspondence: Dr. Olga A. Iakoubova, Celera, Inc., 1401 Harbor Bay Parkway, Alameda, California 94502. (Email: olga.iakoubova{at}celera.com).

Objectives: We asked whether 35 genetic polymorphisms, previously found to be associated with cardiovascular disease, were associated with myocardial infarction (MI) in the CARE (Cholesterol and Recurrent Events) trial and with coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary Prevention Study) trial and whether the risk associated with these polymorphisms could be reduced by pravastatin treatment.

Background: Identification of genetic polymorphisms associated with CHD may improve assessment of CHD risk and understanding of disease pathophysiology.

Methods: We tested the association between genotype and recurrent MI in the CARE study and between genotype and primary CHD in the WOSCOPS trial using regression models that adjusted for conventional risk factors: Cox proportional hazards models for the CARE study and conditional logistic regression models for a nested case-control study of the WOSCOPS trial.

Results: We found that Trp719Arg (rs20455) in KIF6 was associated with coronary events. KIF6 encodes kinesin-like protein 6, a member of the molecular motor superfamily. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had a hazard ratio of 1.50 (95% confidence interval [CI] 1.05 to 2.15) in the CARE trial and an odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial.

Conclusions: In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.

Abbreviations and Acronyms   CHD = coronary heart disease   CI = confidence interval   DNA = deoxyribonucleic acid   HDL-C = high-density lipoprotein cholesterol   HR = hazard ratio   LDL-C = low-density lipoprotein cholesterol   MI = myocardial infarction   OR = odds ratio   SNP = single nucleotide polymorphism

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