Abstract 906: KIF6 Genetic Variant Predicts Effect of Intensive Statin Therapy on Death and Cardiovascular Events in the PROVE IT-TIMI 22 Trial
BACKGROUND: Genetic diversity can result in differential risk of disease and differential response to therapy in patients. The 719Arg variant of kinesin-like protein 6 (KIF6, a member of a family of molecular motors involved in intracellular transport) has been previously associated with increased risk of coronary events and greater benefit from pravastatin vs. placebo in the CARE and WOSCOPS trials. We therefore hypothesized that the benefit of intensive vs. moderate lipid-lowering therapy would be greater in carriers of 719Arg than in noncarriers.
METHODS: We investigated the interaction between KIF6 genotype and benefit of intensive statin therapy on reducing death and major CV events in 1778 patients in PROVE-IT TIMI 22, a randomized trial of high-dose atorvastatin (80mg) vs. standard-dose pravastatin (40mg) in patients with acute coronary syndromes. Cox proportional hazards models were used to adjust for traditional risk factors.
RESULTS: Benefit from intensive statin therapy was significantly greater in KIF6 719Arg carriers (hazard ratio 0.59, 95% CI 0.45– 0.77) than in noncarriers (hazard ratio 0.94, 95% CI 0.70 –1.22): P=0.018 for interaction between 719Arg carrier status and treatment. Carriers and noncarriers did not differ in achieved LDL cholesterol, C-reactive protein (CRP), or triglyceride levels.
CONCLUSIONS: Carriers of 719Arg (59% of the population) receive significantly greater benefit from intensive statin therapy than do noncarriers, a superior benefit achieved through a mechanism distinct from lipid- or CRP-lowering. Functional studies of the KIF6 kinesin are warranted given the consistent relationship between Trp719Arg and statin benefit.