No Impact of KIF6 Genotype on Vascular Risk and Statin Response Among 18,348 Randomized Patients in the Heart Protection Study

Study Questions:

What is the effect of a common KIF6 gene variant on the risk of vascular events and response to statin therapy?

Methods:

Participants received 40 mg simvastatin for 4-6 weeks before being randomly allocated to 40 mg simvastatin daily or placebo for 5 years. Major coronary events were predefined as coronary death or nonfatal myocardial infarction (MI), and major vascular events were predefined as a 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% (p = 5.3 x 10-10) in carriers (Arg/Arg or Trp/Arg), and 24% (p = 4.6 x 10-9) in noncarriers (Trp/Trp). A similar lack of interaction was observed for major coronary events, revascularizations, and strokes considered separately.

Conclusions:

The authors concluded that statin therapy significantly reduces the incidence of coronary and other major vascular events to a similar extent, irrespective of KIF6 genotype, and that KIF6 genotyping to guide statin therapy is not warranted.

Perspective:

Some previous studies have demonstrated that the KIF6 719Arg allele is associated with a 50% higher risk of vascular events compared to noncarriers of this allele. Several studies have also shown that noncarriers of this allele do not benefit from statin therapy to the same extent as carriers. Based on these results, genotyping for KIF6 has been promoted to be useful in determining which patients should be treated with statins. Since 40% of whites are noncarriers, many patients could be deemed unsuitable for statin therapy. Although this sounds like a cost-effective application of personalized medicine, the current study indicates that the association between KIF6 and statin response is not robust, and that using this genetic information in treatment decisions could lead to harm by depriving patients of beneficial therapy.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Cholesterol, Myocardial Infarction, Stroke, Biological Markers, Cardiovascular Diseases, Genotype


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