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The 719Arg variant of KIF6 and cardiovascular outcomes in statin-treated, stable coronary patients of the treating to
Benoit J Arsenault1, S Matthijs Boekholdt, G Kees Hovingh
1Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Insights
The KIF6 719Arg genetic variant does not increase cardiovascular risk. Carriers of this variant did not show consistent benefits from high-dose statin therapy compared to non-carriers in large clinical trials.
Area of Science:
- Genetics and Cardiovascular Disease
- Pharmacogenomics
- Clinical Trial Analysis
Background:
- The KIF6 719Arg variant (rs20455) has been investigated for its potential association with cardiovascular disease (CVD) risk.
- Previous hypotheses suggested carriers might face higher CVD risk and greater benefit from statin therapy.
Purpose of the Study:
- To determine if carriers of the KIF6 719Arg genetic variant are at increased cardiovascular risk.
- To assess whether KIF6 719Arg carriers gain more benefit from high-dose statin therapy compared to non-carriers.
Main Methods:
- Analysis of two large randomized clinical trials: Treating to New Targets (TNT) and Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL).
- Cox proportional hazard models were used to compare major cardiovascular events between high-dose (80 mg/d atorvastatin) and lower-dose statin regimens.
- Patient groups were stratified by KIF6 719Arg allele carrier status (non-carriers, heterozygotes, homozygotes).
Main Results:
- In the TNT study, carriers of two minor alleles showed a significant risk reduction (HR: 0.44) with high-dose atorvastatin.
- However, overall interaction terms for carrier status by treatment were non-significant in both TNT (P=0.810) and IDEAL (P=0.909).
- Heterozygotes and homozygotes for the minor allele were not found to be at increased cardiovascular risk compared to non-carriers.
Conclusions:
- In large randomized trials, KIF6 719Arg allele carriers were not identified as having increased cardiovascular risk.
- Consistent cardiovascular benefit from high-dose statin therapy was not observed in carriers compared to non-carriers.
Background:
Carriers of the KIF6 719Arg variant may be at increased risk for CVD and may benefit more from statin therapy, in terms of CVD risk reduction, than noncarriers. Our objective was to investigate whether carriers of the KIF6 719Arg genetic variant (rs20455) are at increased cardiovascular risk and obtain more benefit from high-dose statin therapy than do noncarriers.
Methods And Results:
We used an adjusted Cox proportional hazard model to assess the hazard ratio (HR) for the reduction of major cardiovascular events by 80 mg/d atorvastatin over 10 mg/d atorvastatin in 4599 patients of the Treating to New Targets (TNT) study and by 80 mg/d atorvastatin over 20-40 mg/d simvastatin in 6541 patients of the Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) study. A total of 381 and 648 patients had a cardiovascular event during follow-up in TNT and IDEAL, respectively. Heterozygotes and homozygotes for the minor allele were not at increased risk compared with noncarriers. In TNT, for noncarriers of the 719Arg allele, the HR for high- versus low-dose atorvastatin was 0.81 (95% confidence interval, 0.59-1.11). In carriers of 1 or 2 minor alleles, the HR was 0.85 (0.66-1.11) and carriers of 2 copies of the minor allele obtained a significant risk reduction (HR: 0.44, 95% confidence interval, 0.23-0.84). In IDEAL, the respective HRs were 0.85 (0.67-1.10), 0.88 (0.62-1.07) and 0.91 (0.58-1.43). The interaction term for carrier status by treatment was also nonsignificant (P=0.810 in TNT and P=0.909 in IDEAL).
Conclusions:
In these 2 large, randomized clinical trials, carriers of the KIF6 719Arg allele were not at increased cardiovascular risk and did not obtain consistent cardiovascular benefit from high-dose statin therapy compared with noncarriers.
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