KIF6 and Coronary Heart Disease: Just How Useful Is This Genetic Marker?

Svati H. Shah, MD; Deepak Voora, MD


January 03, 2011

Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies

Assimes TL, Hólm H, Kathiresan S, et al
J Am Coll Cardiol. 2010;56:1552-1563


A genetic variant in the KIF6 gene has been associated with future coronary heart disease (CHD) events in several observational cohorts and placebo arms of randomized controlled trials.[1,2,3,4,5,6,7]

This variant, which results in an amino acid change from tryptophan to arginine at position 719 in the KIF6 protein, is carried by more than 30% of Caucasians, African-Americans, and Asians, and was associated with an increased risk of CHD events (primarily fatal or nonfatal myocardial infarction [MI]) in these studies. Furthermore, in patients assigned to statin therapy in randomized controlled trials, carriers of the arginine (or high-risk) variant had lower risks of future events than did their control arm counterparts.

These observations form the basis for a commercial test (KIF6-StatinCheck™ Test, Berkeley HeartLab) that tests for this genetic variant as a means to identify patients at increased risk for CHD events independent of traditional risk factors. However, the mechanism by which this genetic variant actually confers increased risk is not known.

In the current study, Assimes and colleagues pooled data from 19 genome-wide association studies (GWAS) of CHD and/or MI encompassing more than 17,000 cases and 39,369 controls in an attempt to better clarify the association between KIF6 and CHD and/or MI.

Because of the stringent statistical criteria required for GWAS (ie, P values < 108), the authors pooled several studies to increase the effective sample size, thus increasing the chances that novel variants might rise above the statistical thresholds required for significance by GWAS. Nevertheless, the authors observed no association with the KIF6 variant and CHD or MI. Furthermore, there was no association in any specific ethnic subgroup or in a subgroup with early onset CHD -- a subgroup that may have a stronger genetic contribution to CHD.


It is important to put these findings into perspective, especially since a commercial test available to physicians is advertised to identify patients at increased risk for CHD/MI beyond traditional risk factors as well as to identify individuals who might benefit most from statin therapy.

Even before the results of this study, it seemed premature to offer genetic testing of KIF6 based on the published observations given the modest risk conferred, lack of functional data, and heterogeneity of type of statin. With these new results in hand, they further call into question the validity of the KIF6 association, and make genetic testing in clinical care even more uncertain.

It should be noted, however, that there are significant differences in the study designs between the work by Assimes and colleagues and the prior literature surrounding KIF6. For example, the current work used a case-control study design for GWAS, whereas the prior KIF6 work used prospective cohort studies. In general, a prospective cohort study design is thought to be superior, since the case-control study design can introduce biases that may interfere with association analyses. That being said, the large sample size in the Assimes study should, in theory, overcome any potential biases of the case-control study design.

Another important distinction is that the outcome of interest may be substantially different between these groups of studies. In the Assimes case-control studies, more than half of the cases were defined as CHD, but in the prior KIF6 literature, the outcome was CHD events. This distinction may seem trivial, but there are likely different pathological mechanisms that drive the development of CHD (eg, coronary artery stenosis, stable angina) vs a CHD event (eg, MI, arrhythmia, and death).

Because there is still insufficient mechanistic data to explain the increased risk observed in carriers of the KIF6 genetic variant, it is unclear whether the differences in association are due to chance, differences in study design, potential confounders, or in outcome definition.

The issue of identifying individuals who might most benefit from statins was not addressed by Assimes and colleagues. Data supporting this premise is based on observations from randomized controlled trials of statin therapy,[2,3,4] but the mechanism behind a potential association between KIF6 and CHD/MI in statin-naïve individuals still remains unknown. It therefore seems premature to use genetic testing for the KIF6 variant with the intention of tailoring statin therapy. Although this remains an exciting possibility, additional research is required before such recommendations can be made. Instead, adherence to evidence-based guidelines for statin therapy,[8] which are due to be updated in 2011, is recommended.



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