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Objectives We asked if carriers of the 719Arg allele of kinesin family member 6 (KIF6) have increased risk of coronary heart disease (CHD) in a cohort of initially healthy Caucasian American women. Background The 719Arg allele of KIF6 (rs20455) has been reported to be associated with increased risk of CHD in a large population-based prospective study, ARIC (Atherosclerosis Risk in Communities), and in the placebo arms of 2 statin trials, CARE (Cholesterol and Recurrent Events) and WOSCOPS (West of Scotland Coronary Prevention Study). However, this KIF6 variant was not specifically investigated in the female subgroup in the ARIC study, and the CARE and WOSCOPS trials included only a small number of female patients. Methods Genotypes of the rs20455 single nucleotide polymorphism (SNP) were determined among 25,283 initially healthy Caucasian women, age 45 years and older, participating in the WHS (Women’s Health Study) who were prospectively followed over a 12-year period for incident cardiovascular events. The risk associated with the 719Arg allele of KIF6 was estimated using Cox proportional hazards models that adjusted for age and traditional risk factors. Results During follow-up, 953 women suffered a first-ever CHD event (myocardial infarction, coronary revascularization, or cardiovascular death) or first-ever ischemic stroke. Compared with noncarriers, carriers of the 719Arg allele had an increased risk of CHD (hazard ratio [HR] = 1.24 [95% confidence interval (CI) 1.04 to 1.46, p = 0.013]) and myocardial infarction (HR = 1.34 [95% CI 1.02 to 1.75, p = 0.034]) but not ischemic stroke. Conclusions Confirming and extending previous reports, carriers of the 719Arg allele of KIF6 have 34% higher risk of myocardial infarction and 24% higher risk of CHD compared with noncarriers among 25,283 women from the WHS.

Polymorphism in KIF6 Gene and Benefit From Statins After Acute Coronary Syndromes: Results from the PROVE IT-TIMI 22 StudyOlga A. Iakoubova, Marc S. Sabatine, Charles M. Rowland, Carmen H. Tong, Jo...

Objectives We asked whether 35 genetic polymorphisms, previously found to be associated with cardiovascular disease, were associated with myocardial infarction (MI) in the CARE (Cholesterol and Recurrent Events) trial and with coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary Prevention Study) trial and whether the risk associated with these polymorphisms could be reduced by pravastatin treatment. Background Identification of genetic polymorphisms associated with CHD may improve assessment of CHD risk and understanding of disease pathophysiology. Methods We tested the association between genotype and recurrent MI in the CARE study and between genotype and primary CHD in the WOSCOPS trial using regression models that adjusted for conventional risk factors: Cox proportional hazards models for the CARE study and conditional logistic regression models for a nested case-control study of the WOSCOPS trial. Results We found that Trp719Arg (rs20455) in KIF6 was associated with coronary events. KIF6 encodes kinesin-like protein 6, a member of the molecular motor superfamily. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had a hazard ratio of 1.50 (95% confidence interval [CI] 1.05 to 2.15) in the CARE trial and an odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial. Conclusions In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.

Numerous strategies to improve statin adherence have been evaluated; however, none have utilized direct patient communication of genetic information as a motivator. This trial is the first to evaluate this novel technique. AKROBATS ([NCT01068834][1]) was a prospective, nonrandomized intervention

To the Editor: To date, the only common genetic variant to consistently associate with risk of coronary artery disease (CAD) or myocardial infarction (MI) is the 9p21.3 variant ([1,2][1]). Several recent reports identified a SNP (rs20455) that alters an amino acid in the KIF6 protein (Trp719Arg)

Objectives The aim of this study was to test the effects of the KIF6 Trp719Arg polymorphism (rs20455) on vascular risk and response to statin therapy in 18,348 participants from the Heart Protection Study. Background There have been claims that noncarriers of the KIF6 719Arg variant receive little benefit from statin therapy. Screening for this genetic variant is now being used to influence statin use. Methods Participants received 40 mg simvastatin daily for 4 to 6 weeks before being randomly allocated 40 mg simvastatin daily or placebo for 5 years. Major coronary event was pre-defined as coronary death or nonfatal myocardial infarction, and major vascular event was pre-defined as major coronary event plus revascularization or stroke. Results The KIF6 genotype was not significantly associated, among placebo-allocated participants, with the risks of incident major vascular events, major coronary events, revascularizations, or strokes. Overall, 40 mg simvastatin daily produced a 42% reduction in low-density lipoprotein cholesterol, which did not differ significantly by KIF6 719Arg carrier status (p = 0.51). Proportional reductions in the risk of major vascular events with statin therapy were similar (interaction p = 0.70) and highly significant across KIF6 genotypes: 23% (95% confidence interval: 16% to 29%; p = 5.3 × 10−10) in carriers (Arg/Arg or Trp/Arg), and 24% (95% confidence interval: 17% to 31%; p = 4.6 × 10−9) in noncarriers (Trp/Trp). A similar lack of interaction was observed for major coronary events, revascularizations, and strokes considered separately. Conclusions Statin therapy significantly reduces the incidence of coronary and other major vascular events to a similar extent, irrespective of KIF6 genotype. Consequently, the use of KIF6 genotyping to guide statin therapy is not warranted. (Heart Protection Study; ISRCTN48489393)

Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation

We read with interest the editorial comment ([1][1]) accompanying 3 reports that described the association of the 719Arg allele of KIF6 with both increased risk of coronary heart disease and with response to statin treatment ([2–4][2]). However, we would like to comment on 2 assertions made in