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MP 2.04.67 KIF6 Genotyping for Predicting Cardiovascular Risk and/or Effectiveness of Statin Therapy

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/2:2015
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


The KIF6 protein belongs to the kinesin superfamily of proteins involved in intracellular transport. The exact function of the KIF6 gene product is as yet undetermined. It has been reported that the gene is not expressed in the vasculature, the primary site of atherosclerosis. Rather, it is expressed in low levels in the brain, connective tissue, colon, eye, pharynx, skin, and testes.(1) In contrast, a study presented at the American Heart Association Arteriosclerosis, Thrombosis and Vascular Biology 2010 Scientific Sessions reported data derived from tissue immunohistochemistry, locating KIF6 protein in macrophages surrounding neovessels and in foam cells in human atherosclerotic lesions.(2) Nevertheless, there is as yet no strong evidence that KIF6 protein plays a direct biological role in atherosclerosis, lipid metabolism, coronary artery disease (CAD), or myocardial infarction (MI).

Analysis of prospective observational studies of cardiovascular health and of the placebo arm of randomized controlled trials (RCTs) of statin intervention in at-risk populations has suggested a significant association between the Trp719Arg single nucleotide polymorphism (SNP; rs20455) in kinesin-like protein 6 (KIF6) and the development of clinical CAD. Approximately 60% of the population carries the putative KIF6 high-risk 719Arg allele. Moreover, carriers of the 719Arg allele in the treatment arms of the statin trials appeared to be at no increased risk, or at decreased risk, of CAD or recurrent MI, depending on the intensity of the statin therapy. These results supported the development of a KIF6 Trp719Arg genotyping test for use as a predictor of CAD risk and of the likely effectiveness of statin therapy.

Celera Corporation, now a wholly owned subsidiary of Quest Diagnostics, Inc., holds a U.S. patent related to methods of determining heart attack risk by detecting the KIF6 gene variant and reduction of such increased risk by statin therapy, and offers the “Cardio IQ™ KIF6 Genotype.” Celera's Berkeley HeartLab subsidiary has been offering KIF6 genotyping (KIF6-StatinCheck™ Genotype Test) since July 2008, and now offers it as part of a comprehensive cardiovascular risk screening program with other serum-based tests. San Francisco General Hospital’s Clinical Chemistry Laboratory (University of California, San Francisco), is the only non-Celera lab to obtain a license to develop a KIF6 LTD; a small number of clinical labs/health care groups have negotiated with Celera to offer the test by sending it to Berkeley HeartLab (eg, Aurora Health Care of Milwaukee, WI).

Regulatory Status

The KIF6 genotyping test is not a manufactured test kit and has not been reviewed by FDA. Rather, it is a laboratory-developed test, offered by clinical laboratories licensed under Clinical Laboratory Improvement Amendments for high-complexity testing. The company submitted a Premarket Approval application to FDA in January 2011, for their KIF6 Genotyping Assay performed on Abbott's m2000™ instrument system. However, on April 7, FDA sent a letter to Celera indicating that its application is not approvable “without major amendment.” The data and publications submitted were deemed “insufficient to demonstrate the safety and effectiveness of the device for its proposed intended use.” The agency indicated that additional data on clinical utility may be required, which could include conducting a randomized controlled clinical trial. As of the current update, there appears to be no further action on this front.


 KIF6 Genotyping is considered investigational for predicting cardiovascular risk and/or the effectiveness of statin therapy.

Policy Guidelines 

There is currently no specific CPT code for this testing. Beginning in 2013, the unlisted molecular pathology code (81479) would be reported.

Prior to 2013, a combination of the molecular diagnostic CPT codes (83890-83912) or unlisted CPT code 84999 would have most likely been used. For example, one laboratory website listed the following codes for this test: 83891, 83892, 83896, 83898, 83903, 83912.

Benefit Application
BlueCard/National Account Issues

None identified


This policy was created with a systematic review of the literature in January 2011 and updated periodically with literature reviews, most recently through January 5, 2015.

Analytic validity

The KIF6 Trp719Arg SNP is assessed through real-time polymerase chain reaction, with PCR amplification of target sequences from genomic DNA, followed by allele-specific oligonucleotide ligation. No studies were identified that specifically addressed the analytic validity of available assays for the KIF6 Trp719Arg SNP. One study reported that the fraction of samples with successful genotype determination was 97.9%.(3)

Clinical validity

The association between the KIF6 Trp719Arg SNP and coronary artery disease (CAD) or coronary heart disease (CHD) outcomes was investigated in retrospective evaluations of prospective, observational studies (see Table 1, part 1),(3-5) and in retrospective evaluations of the placebo arms of randomized controlled trials (RCTs) of statin therapy (see Table 1, part 2).(6,7) Whether the initial inclusion of KIF6 markers in early studies initiated by Celera was based on candidate gene selection or on larger, gene-scanning studies is unclear from the published literature, and claims of critics and test developers on this point are contradictory.

In both relatively unselected prevention cohorts (see Table 1, part 1), and in trial populations selected for high risk of a CHD event, the Trp719Arg SNP is significantly associated with CHD outcomes at hazard ratios (HRs) in the range of approximately 1.1 to 1.5.

In the statin treatment arms of RCTs, carriers of the 719Arg variant were at decreased risk of an event compared with controls, whereas noncarriers appeared to derive little if any benefit from statin treatment. In the analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 trial, which compared less intensive (pravastatin) versus more intensive (atorvastatin) therapy, carriers of the 719Arg variant received significantly greater benefit from intensive therapy than noncarriers.(8)

However, a large meta-analysis of 19 case-control studies (see Table 1, part 3)(9) found no association between the Trp719Arg SNP and CAD, even when the overall population was restricted to Europeans with early onset disease (less likely to be confounded by statin therapy), to Europeans with (MI, or to Europeans with early onset MI. The authors of the meta-analysis note that they examined only nonfatal MI; if the Trp719Arg variant increases the risk of fatal CAD more than the risk of nonfatal CAD, the study results could be biased toward the null. The meta-analysis could not examine whether the effect on risk was modified by statin therapy.

In addition to the findings of the meta-analysis, none of the several, large genome-wide association studies for CAD or MI reported any SNPs at the KIF6 locus as significant.(10-14) For this reason, some have considered the possible candidate (ie, preselected) gene approach to the KIF6 variant analysis by the test developers as potentially flawed, given the current lack of biologic plausibility.

Evidence published from 2011-2012 (see Table 1, part 4) is consistent with the meta-analysis results. Ridker et al(15) evaluated the effect of the KIF6 variant on the outcomes of 8781 Caucasian trial participants in the JUPITER (Justification for Use of Statins in Primary Prevention, An Intervention Trial Evaluating Rosuvastatin) study and in the trial as a whole. Rosuvastatin was equally effective at reducing cardiovascular event rates among carriers and noncarriers of the KIF6 variant; results for trial participants as a whole were essentially identical. Hopewell et al(16) evaluated data from the Heart Protection Study on more than 18,000 patients with prior cardiovascular disease or high predisposing risk and compared outcomes after treatment with simvastatin or placebo. The authors reported no association of KIF6 variant status with outcome in the placebo arm, nor in the treatment arm—simvastatin reduced the incidence of coronary events equally regardless of KIF6 status. Hoffmann et al(17) evaluated a narrowly focused population of patients with type 2 diabetes and less than 2 years of previous treatment by hemodialysis, randomly assigned to double-blinded treatment with either 20 mg of atorvastatin (n=619) or placebo (n=636). In neither the placebo nor the statin group was there any association of KIF6 genotype with major cardiovascular events. This study was limited because statins did not achieve the expected improvement in survival, despite significantly decreasing low-density lipoprotein (LDL) cholesterol. Nevertheless, taken together, these 3 studies show that in different populations with different levels of vascular risk and treated with different statin drugs, there was nomeasureable effect of the KIF6 variant on statin response nor any association with vascular risk.

Another study, by Arsenault et al(18) investigated whether carriers of the KIF6 variant obtain more benefit from high-dose statin therapy than do noncarriers by retrospective analysis of 2 prospective trials. In the Treating to New Targets (TNT) study, 4599 patients with stable CHD and LDL cholesterol levels less than 130 mg/dL, randomly assigned to receive either 10- or 80-mg of atorvastatin per day and followed up for a median of 4.9 years, were genotyped. KIF6 genotype did not affect risk for future events within treatment arms. Genotype subgroups had a similar benefit from 80 mg atorvastatin compared with 10 mg, except for the homozygous variant subgroup, which was the only group with a statistically significant benefit from the higher statin dose, but interaction for genotype by treatment was not significant. The Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) study enrolled patients with a history of MI and randomized them to high-dose atorvastatin or usual dose simvastatin and followed them for a median of 4.8 years. Of the 8888 enrolled, 6541 were genotyped; there were no significant differences by KIF6 genotype in comparative response to statin treatment, and the interaction for genotype by treatment was not significant.

A retrospective evaluation of PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial participants found a significant relationship between KIF6 variant homozygotes and fatal or nonfatal MI or stroke only in women on pravastatin (see Table 1), which lost significance after correction for multiple comparisons.(19) The study authors also reported that homozygous carriers of the KIF6 variant were significantly less responsive to pravastatin, but did not recommend the use of KIF6 testing to determine statin use.

The conflicting results regarding the KIF6 variant, CHD, and treatment outcomes appears to have been explained in a meta-analysis by Ference et al(20) The authors included 37 case-control studies, prospective cohort studies, or randomized trial treatment allocation arms (each considered as a separate cohort), which together enrolled 144,931 participants and reported 27,465 CHD events. The KIF6 genotype, and, in particular, the Trp719Arg SNP carrier status, was not associated with increased risk of CHD event. A new analysis resulted in evidence of KIF6 variant effect modification. For each mmol/L increase in LDL cholesterol, KIF6 variant carriers experienced a 15% greater increase in the relative risk of CHD, as compared with noncarriers (ratio of risk ratio [RR]=1.15; 95% confidence interval [CI], 1.06 to 1.25, p=0.001). Similarly, the decrease in risk for each mmol/L decrease in LDL was 13% greater for variant carriers. Also included in the meta-analysis were 8 randomized trials of statin therapy, involving 50,060 participants and 7307 CHD events. KIF6 variant carriers derived a greater clinical benefit for each mmol/L reduction in LDL cholesterol during treatment with a statin than did noncarriers (ratio of RR=0.87; 95% CI, 0.77 to 0.99; p=0.038). Thus, the results suggest that the KIF6 Trp719Arg variant increases vulnerability to LDL cholesterol. This may explain why KIF6 variant carriers appear to derive greater clinical benefit from a statin even though the variant does not appear to affect the ability of the statin to lower LDL cholesterol, nor does it appear, on average, to be independently associated with the risk of CHD. However, “the association between the KIF6 variant and the risk of CHD will vary according to the average LDL cholesterol level of the population(s) under study.”(20) This may help explain some of the conflicting reports of KIF6 genotype association with CHD.

Table 1. Results of Individual Studies Investigating Differential Effects of KIF6 Genotype on Cardiovascular Outcomes and Meta-Analysis of the Association of KIF6 With CAD Outcomes


Patients Evaluated

KIF6 Association Evaluated

Results: Observational Study or Placebo Arm, KIF6V Carriers vs Noncarriers

Results: Statin Arm vs Placebo Arm (unless otherwise stated)

Part 1. KIF6 variant association with CAD outcomes in retrospective evaluations of prospective, observational studies

Morrison et al (2007) Retrospective evaluation of ARIC study4

U.S. individuals ages 45-64 y

MI, CHD death, or coronary revascularization


(95% CI,1.00 to 1.19)


Shiffman et al (2008) Retrospective evaluation of CHS5

Adults ages ≥65 y

Incident MI


(90% CI, 1.1 to 1.52)a

(95% CI, 1.06 to 1.6)b


Shiffman et al (2008) Retrospective evaluation of WHS3

Healthy Caucasian American women

Incident CHD event (MI,coronary revascularization, or CVrelated death) or incident ischemic stroke

CHD HR=1.24 (95% CI, 1.04 to 1.46)

MI HR=1.34 (95% CI, 1.02 to 1.75)

Stroke HR=NS


Part 2. KIF6 variant association with CAD outcomes in retrospective evaluations of RCTs of statin therapy

Iakoubova et al (2008) Retrospective evaluation of CARE study7

Caucasian MI survivors with total cholesterol <240 mg/dL

Recurrent fatal or nonfatal MI


(95% CI, 1.05 to 2.15)

Among KIF6V carriers: HR=0.63 (0.46 to 0.87)

Among noncarriers: HR=0.80 (0.52 to 1.24)

Shiffman et al (2010) Retrospective evaluation of CARE study21

MI survivors (all ethnicities) with total cholesterol <240 mg/dL

Recurrent fatal or nonfatal MI


Adjusted for self-reported ethnicity, among KIF6V carriers: HR=0.63 (0.49 to 0.83)

Among noncarriers: HR=1.01 (0.69 to 1.45)

Iakoubova et al (2008) Nested case-control study from WOSCOPS trial7

Men with hyper-cholesterolemia but no history of MI

Nonfatal MI, revascularization procedures, or death from CHD

OR=1.55 (95% CI, 1.14 to 2.09)

Among KIF6V carriers: HR=0.50 (0.38 to 0.68)

Among noncarriers: HR=0.91 (0.64 to 1.28)

Iakoubova et al (2008) Retrospective evaluation of PROVE IT-TIMI 228

Patients hospitalized for MI or high-risk unstable angina

Composite end point: all-cause mortality, MI, unstable angina, or stroke

No placebo arm

Intensive vs moderate statin therapy arms among:

KIF6V carriers HR=0.59 (0.45 to 0.77)

Non-KIF6V carriers HR=0.94 (0.70 to 1.27)

Iakoubova et al (2010) Retrospective evaluation of PROSPER study6

Older patients with preexisting vascular disease

Older patients at increased risk for vascular disease

Composite end point: death from CHD, nonfatal MI, or fatal/ nonfatal stroke

HR=1.28 (95% CI, 0.98 to 1.69)

Among KIF6V carriers: HR=0.66 (0.52 to 0.86)

Among noncarriers: HR=0.94 (0.69 to 1.28)

No benefit

Part 3. Meta-analysis of KIF6 variant association with CAD outcomes

Assimes et al (2010) Meta-analysis of 19 case-control studies9

(Various) 17,000 cases, 39,369 controls

CAD cases with and without a diagnosis of nonfatal MI

OR=0.98 (95% CI, 0.95 to 1.02)



Europeans, subgroup with very early onset disease

As above

OR=0.99 (95% CI, 0.94 to 1.04)



Europeans, restricting cases to MI

As above

OR=0.99 (95% CI, 0.96 to 1.03)



Europeans, restricting cases to early onset MI

As above

OR=1.03 (95% CI, 0.98 to 1.09)


Part 4. Recent publications: KIF6 variant association with CAD outcomes in retrospective evaluations of RCTs of statin therapy

Ridker et al (2011) Retrospective evaluation of prospective JUPITER study15 Rosuvastatin vs placebo

Men and women free of diabetes or prior cardiovascular disease

Composite: CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or arterial revascularization

HR=0.91 (95% CI, 0.66 to 1.26)

Among KIF6V carriers: HR=0.61 (0.43 to 0.87)

Among noncarriers: HR=0.59 (0.39 to 0.88) P interact, 0.90

Hopewell et al (2011) Retrospective evaluation of prospective Heart Protection Study16 Simvastatin vs placebo

Individuals at high risk for or a previous diagnosis of CV disease

Composite: CHD death, nonfatal MI, strokes, coronary or noncoronary revascularizations

No significant effect on risk of major CV events, regardless of modeling approach (p range, 0.54-0.76)

Among KIF6V carriers: 23% (16% to 29%)

Among noncarriers: 24% (17% to 31%) P interact, 0.4-0.7

Hoffmann et al (2011) Retrospective evaluation of 4D prospective study17 Atorvastatin vs placebo

Patients with T2DM and <2 y prior hemodialysis treatment

Composite: death from cardiac causes, MI, or stroke

HR=0.83 (95% CI, 0.66 to 1.05)

Among statin-treated, KIF6V carriers vs noncarriers:

HR=0.96 (0.76 to 1.23)

Arsenault et al (2011) Retrospective evaluation of prospective TNT (80-vs 10-mg/d atorvastatin) and IDEAL (80 mg/d atorvastatin vs 20-40 mg/d simvastatin) studies18

TNT: patients with stable CHD and LDL-C levels <130 mg/dL

IDEAL: patients with a history of MI

Composite: coronary death, nonfatal MI, resuscitation after cardiac arrest and fatal or nonfatal stroke


Among KIF6V carriers: 0.85 (0.66 to 1.11)

Among homozygote carriers: 0.44 (0.23 to 0.84)

Among noncarriers: 0.81 (0.59 to 1.11) P interact, 0.81

Among KIF6V carriers: 0.91 (0.58 to 1.43)

Among homozygote carriers: 0.88 (0.62 to 1.07)

Among noncarriers: 0.85 (0.67 to 1.10),P interact, 0.91

Akao et al (2012) Retrospective study of participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial,(19) randomized to pravastatin 40 mg/d or placebo

Individuals with a history of, or risk factors for, vascular disease

MI or stroke

Homozygote HR=0.47 (p=0.03) For women on pravastatin only; not significant after correction for multiple



ARIC: Atherosclerosis Risk in Communities cohort; CAD: coronary artery disease; CARE: Cholesterol and Recurrent Events trial;
CHD: coronary heart disease; CHS: Cardiovascular Health Study; CI: confidence interval; CV: cardiovascular; HR: hazard ratio;
IDEAL: Incremental Decrease in End Points Through Aggressive Lipid-Lowering; JUPITER: Justification for Use of Statins in Primary Prevention, An Intervention Trial Evaluating Rosuvastatin; LDL-C: low-density lipoprotein cholesterol; MI: myocardial infarction; NA: not applicable; OR: odds ratio; PROSPER: PROspective Study of Pravastatin in the Elderly at Risk; PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 trial; RCT: randomized controlled trial; TNT: treating to new targets; T2DM: type 2 diabetes mellitus; WHS: Women's Health Study; WOSCOPS: West of Scotland Coronary Prevention Study.
a Published.
b Calculated from published data.

Clinical Utility

Based on the earlier retrospective analyses of statin trials, and the apparent association of the Trp719Arg variant with treatment benefit, genotyping was recommended to predict which patients would most benefit from pravastatin or atorvastatin treatment. For carriers of the KIF6 variant, the number needed to treat (NNT) to prevent 1 event is approximately 10 to 20, whereas for noncarriers, the NNT is approximately 80
to more than 100.(22) Thus, it has been suggested that for patients at clinically high risk who are noncarriers, additional intervention may be appropriate; for variant carriers at clinically lower risk who might not normally be treated, statin treatment may provide greater than average benefit. However, these management changes have not been tested prospectively. The more recent retrospective evaluations of prospective, randomized trials (Table 1, part 4), conducted in large patient populations, indicate that noncarriers of the KIF6 variant benefit from statin therapy to the same degree as variant carriers, likely invalidating the rationale for genotyping and basing statin treatment recommendations on the test result.(23) In a 2014 prospective study evaluating the association between KIF6 genotype status and serum lipids in a cohort of 235 Filipino-American women, there was no association between KIF6 variant status and likelihood of elevated LDL-C levels in both statin-treated and non-statin-treated patients.(24)

Celera has been working with pharmacy benefit manager Medco to generate real-world evidence regarding patient knowledge of KIF6 genotype status and statin compliance. The prospective “Additional KIF6 Risk Offers Better Adherence to Statins” (AKROBATS) trial (NCT01068834) was a prospective, nonrandomized, open-label, single-center trial designed to compare statin adherence at 6 months in those who learn about their KIF6 carrier status versus those who do not. Results were published in 2013 by Charland et al.(25) The study authors conducted a quasi-experimental study design, using Medco’s prescription claims database to identify potentially eligible patients who were defined as patients older than 18 years who were new to statin therapy (with no pharmacy electronic claims for atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin ± ezetimibe in the 6 months before the initial statin fill date). KIF6 genotyping was performed on a self-collected buccal cell sample that was mailed by subjects back to the testing lab. Tested patients were mailed their KIF6-carrier status results and a printed information sheet that provided information about KIF6 carriers and noncarriers and coronary heart disease risk reduction.

The primary control group for the study comprised patients in the Medco database who were not contacted for study participation, but who satisfied eligibility criteria. Control subjects were matched 1:1 with the final KIF6-tested group based on age, sex, index statin pharmacy channel (mail or retail), and number of unique chronic medications within 180 days of the statin index date. A secondary control cohort was created from patients who were contacted about the study and made aware that their statin adherence might be routinely monitored but who declined study participation with KIF6 testing. Of 24,134 potentially eligible patients with new statin therapy claims from March 1, 2010, to October 31, 2010, 1509 were contacted for participation, of whom 688 consented to participate and 821 refused. Of those who consented, 647 had a verified statin claim, did not have an unknown number of days between statin index date and study contact, and had a KIF6 test result received within 30 days of the study call, and were included in the analysis. There were 647 matched control patients in the primary control group. Of the 821 who declined study participation, 779 were included in the secondary control group. The primary study outcomes were statin prescription adherence and persistence, assessed using prescription claims records. Adherence was calculated as the proportion of days covered; subjects were adherent if they had 80% or more of days covered. The KIF6-tested group was similar to the primary control group for the matched variables (age, sex, index statin prescription fill channel or baseline number of chronic medications) and in marital status, education, income, cardiovascular medications including aspirin, and smoking status, but had a significantly lower prevalence of hypertension, diabetes, heart failure, and different geographical distribution. The KIF6-tested group also differed significantly from the secondary cohort group at baseline: secondary controls were older, were less educated, had a lower income, and had greater comorbidities and cardiovascular medication use.

The unadjusted mean proportion of days covered with statin therapy at 6 months was significantly higher in the KIF6-tested cohort than in the matched controls (0.79 [95% CI, 0.77 to 0.81] vs 0.68 [95% CI, 0.66 to 0.70], respectively, p<0.001).The proportion categorized as adherent to statin therapy was 18.4% higher for the KIF6-testing group (63.4%; 95% CI, 59.6% to 67.1%) compared with matched controls (45.0%; 95% CI, 41.1% to 48.8%; p<0.001), and 12.7% higher compared with the secondary control group (50.7%; 95% CI, 47.7% to 52.6%; p<0.001]). While this study reports an association between receipt of KIF6-genotype testing results and higher statin adherence, the nonrandomized study design and the baseline group differences limit the validity of the results. Potential for bias in the self-selection of healthier patients for KIF6 genotyping and the inability to isolate the incremental effects of receiving the KIF6 genotype results over other aspects of study participation limit the conclusions that can be drawn about the effect of KIF6 genotyping on adherence.

Ongoing and Unpublished Clinical Trials

The Genetic Risk Stratification to Identify Individuals for Early Statin Therapy study was funded under the American Recovery and Reinvestment Act of 2009 Investments in Coronary Artery Disease (Project No. 1RC1HL099634-01). Goals of the study are to (1) test whether specific panels of genetic variants identify patients who experience a greater clinical benefit with statin therapy using retrospective data; and (2) test whether specific panels of genetic variants identify patients who experience a higher risk of statin-induced adverse effects in the same cohorts. This retrospective data analysis project was due to be completed in August 2011, but no updated information has been identified.

A search of in January 2015 identified no ongoing trials specifically evaluating the role of KIF6 genotyping in predicting cardiovascular risk or response to statin therapy.

Summary of Evidence

Data supporting the association of the KIF6 rs20455 single nucleotide polymorphism, corresponding to an arginine-to-tryptophan substitution at position 719 (Trp719Arg), with coronary artery disease (CAD) outcomes are contradictory. The most recent evidence from large populations at different levels of vascular risk does not support a significant association with future CAD outcomes. Moreover, the biologic function of the KIF6 gene product is currently unknown. Thus, the clinical validity for the KIF6 genotyping test has not been shown. The most recent analyses of treatment trials indicate that the efficacy of statin treatment appears to be similar in carriers and noncarriers of the mutation. A large meta-analysis shows that KIF6 variant carriers derive greater clinical benefit from low-density lipoprotein cholesterol reduction compared with noncarriers by about 13%. One nonrandomized study suggested that subjects who received KIF6 genotype results had greater adherence to statin therapy, but methodologic limitations are present in this study, and the findings have not been evaluated in randomized trials. Further, it has not been determined whether knowledge of carrier status can be used to improve patient management decisions and improve outcomes in other ways. Thus, testing for KIF6 status to determine statin treatment benefit is considered investigational.

Practice Guidelines and Position Statements

No reference to KIF6 was found in the 2010 American College of Cardiology (ACC) Foundation/American Heart Association (AHA) Practice Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adult.(26,27)

In 2013, ACC/AHA Task Force on Practice Guidelines issued a guideline on the assessment of cardiovascular risk which does not address KIF6 genotyping.(28)

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for KIF6 genotyping in coronary heart disease risk or the selection or use of statin therapy have been identified.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

Palmetto GBA determines coverage and reimbursement for laboratories that perform molecular diagnostic testing and submit claims to Medicare in Medicare Jurisdiction E (California, Nevada, and Hawaii). Palmetto GBA’s decisions apply for all molecular diagnostic tests for Medicare. In 2014, Palmetto GBA completed a review on the KIF6 genotype test, and concluded, “To date, there is insufficient evidence to support the required clinical utility for the established Medicare benefit category. Therefore, the KIF6 genotype test is a statutorily excluded test.”(29)Hoffmann MM, Marz W, Genser B, et al. Lack of association between the Trp719Arg polymorphism in kinesinlike protein-6 and cardiovascular risk and efficacy of atorvastatin among subjects with diabetes on dialysis: The 4D study. Atherosclerosis. Dec 2011;219(2):659-662. PMID 21871624



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  14. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. Jun 7 2007;447(7145):661-678. PMID 17554300
  15. Ridker PM, MacFadyen JG, Glynn RJ, et al. Kinesin-like protein 6 (KIF6) polymorphism and the efficacy of rosuvastatin in primary prevention. Circ Cardiovasc Genet. Jun 2011;4(3):312-317. PMID 21493817
  16. Hopewell JC, Parish S, Clarke R, et al. No impact of KIF6 genotype on vascular risk and statin response among 18,348 randomized patients in the heart protection study. J Am Coll Cardiol. May 17 2011;57(20):2000-2007. PMID 21458191
  17. Arsenault BJ, Boekholdt SM, Hovingh GK, et al. The 719Arg Variant of KIF6 and Cardiovascular Outcomes in Statin-Treated, Stable Coronary Patients of the TNT and IDEAL Prospective Studies. Circ Cardiovasc Genet. Dec 1 2011. PMID 22135385
  18. Akao H, Polisecki E, Kajinami K, et al. KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly. Atherosclerosis. Feb 2012;220(2):456-462. PMID 22192511
  19. Ference BA, Yoo W, Flack JM, et al. A common KIF6 polymorphism increases vulnerability to low-density lipoprotein cholesterol: two meta-analyses and a meta-regression analysis. PLoS One. 2011;6(12):e28834. PMID 22216121
  20. Shiffman D, Sabatine MS, Louie JZ, et al. Effect of pravastatin therapy on coronary events in carriers of the KIF6 719Arg allele from the cholesterol and recurrent events trial. Am J Cardiol. May 1 2010;105(9):1300-1305. PMID 20403483
  21. Li Y, Iakoubova OA, Shiffman D, et al. KIF6 polymorphism as a predictor of risk of coronary events and of clinical event reduction by statin therapy. Am J Cardiol. Oct 1 2010;106(7):994-998. PMID 20854963
  22. Musunuru K. Lack of association of KIF6 genotype with vascular disease and statin response. Circ Cardiovasc Genet. Aug 1 2011;4(4):467-468. PMID 21846872
  23. Ancheta IB, Battie CA, Richard D, et al. The Association between KIF6 Single Nucleotide Polymorphism rs20455 and Serum Lipids in Filipino-American Women. Nurs Res Pract. 2014;2014:328954. PMID 24587901
  24. Charland SL, Agatep BC, Herrera V, et al. Providing patients with pharmacogenetic test results affects adherence to statin therapy: results of the Additional KIF6 Risk Offers Better Adherence to Statins (AKROBATS) trial. Pharmacogenomics J. Aug 27 2013. PMID 23979174
  25. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. Nov 15 2010. PMID 21098428
  26. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Nov 15 2010. PMID
  27. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Jul 1 2014;63(25 Pt B):2935-2959. PMID 24239921
  28. KIF6 Genotype Coding and Billing Guidelines (M00017). 2014; Accessed January 15, 2015.






No specific code; see Policy Guidelines

ICD-9-CM diagnosis


Investigational for all relevant diagnoses

ICD-10-CM (effective 10/1/15)    Investigational for all relevant diagnoses
ICD-10-CM (effective 10/1/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.


Cardiovascular genotyping
Genetic testing, cardiovascular risk
Genetic testing, statin pharmacogenetics
KIF6 genotyping
Pharmacogenetic testing, statins

Policy History
Date Action Reason
08/12/10 Add to Medicine section, Pathology/Laboratory subsection New policy. Considered investigational
02/09/12 Replace policy Policy updated with literature review, references 15-24 added. No change to policy statement.
2/14/13 Replace policy Policy updated with literature review, references 19, 20 added. No change to policy statement
2/13/14 Replace policy Policy updated with literature review through January 3, 2014. Reference 23 added. No change to policy statement.
2/12/15 Repalce policy Policy updated with literature review through January 5, 2015. References 24 and 28-29 added. Policy statement unchanged.