Abstract
BackgroundWe sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol.MethodsWe conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin.ResultsIn a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD (RR: 1.02, 95%CI: 0.98–1.07, p = 0.288). Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers (ratio of RR: 0.87, 95%CI: 0.80–0.94, p = 0.001) agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy (ratio of RR: 0.87, 95%CI: 0.77–0.99, p = 0.038).ConclusionThe KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol.
Highlights
A common single nucleotide polymorphism results in an argine to tryptophan substitution at position 719 (Trp719Arg) in the gene encoding kinesin-like protein 6 (KIF6)
The question arises as to whether it is biologically plausible that carriers of a 719Arg allele could experience a greater clinical benefit from treatment with a statin than non-carriers, if this polymorphism does not have any impact on the low-density lipoprotein (LDL) cholesterol lowering effect of statins, and if this polymorphism is not associated with an increased risk of cardiovascular disease (CVD)
Among the 37 study samples included in our meta-analysis, 19 prospective cohort studies involving a total of 88,535 participants and 9,692 incident CVD events, provided information on the average baseline LDL cholesterol level of the population under study and were included in our meta-regression analysis [1,2,3,4,5,6,10,11,12,13,14,25]
Summary
A common single nucleotide polymorphism (rs20455) results in an argine to tryptophan substitution at position 719 (Trp719Arg) in the gene encoding kinesin-like protein 6 (KIF6). Some [1,2,3,4], but not all [5,6], genetic sub-studies of previously conducted randomized trials of statin therapy have reported that persons who inherit one or more copies of the 719Arg allele experienced a greater reduction in clinical events than non-carriers during treatment with a statin, despite the fact that both carriers and noncarriers experienced similar reductions in low-density lipoprotein (LDL) cholesterol during treatment [4,5,6]. We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol
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