Polymorphism in KIF6 Gene and Benefit From Statins After Acute Coronary Syndromes

Celera, Alameda, California 9450, USA.
Journal of the American College of Cardiology (Impact Factor: 16.5). 02/2008; 51(4):449-55. DOI: 10.1016/j.jacc.2007.10.017
Source: PubMed


We explored whether the benefit of intensive versus moderate statin therapy would be greater in carriers of KIF6 719Arg than in noncarriers.
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.
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.
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.
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.

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Available from: Todd G Kirchgessner, May 16, 2015
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    • "This study is the first to demonstrate differences in cholesterol levels among KIF6 719Arg carriers on statin therapy when compared with 719Arg carriers not taking statins in a sample of MCI and AD patients. These findings are consistent with other studies that have found 719Arg carriers to have significantly lower TC and LDL levels with statin therapy [1] [2] [3] [4] [5] [6]. This study also found that 719Arg carriers not taking statins had the highest TC and LDL levels among the study sample. "
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    ABSTRACT: KIF6 719Arg allele carriers are thought to have a greater lipid lowering response from statin therapy than non-carriers. Given the continued interest in the relationship between cholesterol, statin use, amnestic mild cognitive impairment (aMCI), and Alzheimer's disease (AD), investigating the role of KIF6 719Arg carrier status in these relationships may be of importance. Data from 86 patients (36 aMCI, 50 AD) with an average age of 76.87 ± 8.22 years were used for this study. Total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides were the outcome variables. 719Arg carriers taking statins had significantly lower TC (p < 0.001) and LDL (p < 0.001) levels than 719Arg carriers not taking statins. In addition, 719Arg carriers not taking statins had significantly higher TC (p = 0.004) and LDL (p < 0.001) than 719Arg non-carriers taking statins. Additional analyses indicated that ApoE ε4 carrier status and statin use interaction is also associated with lower TC (p = 0.04), but not LDL (p = 0.06). The interaction between 719Arg and ApoE ε4 carrier status on TC and LDL was not significant. This study is the first to demonstrate an association between lower cholesterol levels and statin use among KIF6 719Arg allele carriers with aMCI and AD. Accounting for 719Arg carrier status may be important in future studies investigating the link between cholesterol and AD and also for AD and aMCI clinical trials using statins as a treatment.
    Full-text · Article · Aug 2012 · Journal of Alzheimer's disease: JAD
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    • "In addition to survival bias, failure to account for statin use may contribute to the weaker association between KIF6 genotypes and CHD in case-control studies. Four studies have thus far demonstrated that statins significantly reduce CHD-risk in carriers of KIF6 719Arg, whereas noncarriers derive less benefit from statins [6,8,10]. This disparity in statin benefit will attenuate the association between incident CHD and KIF6 719Arg in studies that fail to exclude statin users. "
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    ABSTRACT: Case-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival (34% one-year fatality following a coronary attack). A case in point is the KIF6 Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the KIF6 Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using KIF6 Trp719Arg as an example. Ten replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among KIF6 Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between KIF6 genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD.In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the KIF6 719Arg variant, should also attenuate the KIF6 719Arg odds ratio in case-control studies. These computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for KIF6 Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of KIF6 719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.
    Full-text · Article · Mar 2011 · BMC Medical Genetics
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    • "The 719Arg variant was also associated with greater reduction of coronary events from both pravastatin (a hydrophilic statin) and atorvastatin (a lipophilic statin) therapy. In retrospective genetic analyses of four prospective clinical trials, the Cholesterol and Recurrent Events trial (CARE) (Sacks et al. 1996), the West of Scotland Coronary Prevention Study (WOSCOPS) (Shepherd et al. 1995), Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) (Cannon et al. 2004), and the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), carriers of the 719Arg variant (~60% of people of European ancestry) had substantial and significant reduction of CHD events from statin therapy, whereas non-carriers did not (Iakoubova et al. 2008a, b, 2009). "
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    ABSTRACT: A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (Pinteraction < 0.1 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (Pinteraction < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from −4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy. Electronic supplementary material The online version of this article (doi:10.1007/s00439-010-0892-6) contains supplementary material, which is available to authorized users.
    Full-text · Article · Oct 2010 · Human Genetics
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