A common KIF6 polymorphism increases vulnerability to low-density lipoprotein cholesterol: two meta-analyses and a meta-regression analysis.
BACKGROUND
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.


METHODS
We 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.


RESULTS
In 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).


CONCLUSIONS
The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol.
Division of Translational Research and Clinical Epidemiology, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA. bference@med.wayne.edu
Brian A
BA
Ference
Wonsuk
W
Yoo
John M
JM
Flack
Michael
M
Clarke
D008078:Cholesterol, LDL / Q000097:blood / Q000502:physiology*; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D011110:Polymorphism, Genetic; D012044:Regression Analysis
D008078:Cholesterol, LDL; C526774:KIF6 protein, human; D016547:Kinesins