Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study.
OBJECTIVE
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.
Iakoubova
Olga A
OA
Celera, Alameda, California 9450, USA. olga.iakoubova@celera.com
Sabatine
Marc S
MS
Rowland
Charles M
CM
Tong
Carmen H
CH
Catanese
Joseph J
JJ
Ranade
Koustubh
K
Simonsen
Katy L
KL
Kirchgessner
Todd G
TG
Cannon
Christopher P
CP
Devlin
James J
JJ
Braunwald
Eugene
E
D000069059:Atorvastatin; D015331:Cohort Studies; D003327:Coronary Disease / Q000188:drug therapy* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D012307:Risk Factors; D016896:Treatment Outcome
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; C526774:KIF6 protein, human; D016547:Kinesins; D017035:Pravastatin