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CLINICAL RESEARCH: GENETICS AND CORONARY ARTERY DISEASE

Polymorphism in KIF6 Gene and Benefit From Statins After Acute Coronary Syndromes

Results From the PROVE IT-TIMI 22 Study

Olga A. Iakoubova, MD, PhD^_*,_*, Marc S. Sabatine, MD, MPH, FACC, Charles M. Rowland, MS^_*, Carmen H. Tong, BS^_*, Joseph J. Catanese, BS^_*, Koustubh Ranade, PhD, Katy L. Simonsen, PhD, Todd G. Kirchgessner, PhD, Christopher P. Cannon, MD, FACC, James J. Devlin, PhD^_* and Eugene Braunwald, MD, MACC

^_* Celera, Alameda, California
TIMI Study Group, Cardiovascular Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey.

Manuscript received August 13, 2007; revised manuscript received September 28, 2007, accepted October 22, 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 explored whether the benefit of intensive versus moderate statin therapy would be greater in carriers of KIF6 719Arg than in noncarriers.

Background: The 719Arg variant of Trp719Arg (rs20455), a polymorphism in kinesin-like protein 6, is associated with greater risk of coronary events and greater benefit from pravastatin versus placebo.

Methods: We genotyped 1,778 acute coronary syndrome patients within the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22) trial and investigated different intensities of statin therapy in carriers of 719Arg and in noncarriers using Cox proportional hazards models that adjusted for traditional risk factors.

Results: Benefit from intensive, compared with moderate, statin therapy was significantly greater in the 59% of the cohort who were carriers (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.45 to 0.77) than in those who were noncarriers (HR 0.94, 95% CI 0.70 to 1.27; p = 0.018 for interaction between 719Arg carrier status and treatment). Absolute risk reduction was 10.0% in carriers versus 0.8% in noncarriers. The benefit of intensive therapy in carriers was significant as early as day 30 of therapy. Carriers and noncarriers did not differ in on-treatment low-density lipoprotein cholesterol, triglyceride, or C-reactive protein (CRP) levels.

Conclusions: Carriers of 719Arg receive significantly greater benefit from intensive statin therapy than do noncarriers, a superior benefit that appears to be due to a mechanism distinct from lipid or CRP lowering. Functional studies of the KIF6 kinesin are warranted, given the consistent association of Trp719Arg with risk of coronary events and statin benefit.

Abbreviations and Acronyms   CHD = coronary heart disease   CI = confidence interval   CRP = C-reactive protein   HDL-C = high-density lipoprotein cholesterol   HR = hazard ratio   LDL-C = low-density lipoprotein cholesterol

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				O. Iakoubova, J. Shepherd, and F. Sacks Association of the 719Arg variant of KIF6 with both increased risk of coronary events and with greater response to statin therapy. J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2195 - 2195. [Full Text] [PDF]

				A. J. Marian Reply. J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2195 - 2196. [Full Text] [PDF]

				E. Braunwald The Management of Heart Failure: The Past, the Present, and the Future CIRCULATION: HEART FAILURE, May 1, 2008; 1(1): 58 - 62. [Full Text] [PDF]

				A. J. Marian Surprises of the genome and "personalized" medicine. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 456 - 458. [Full Text] [PDF]