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MP 2.04.71 Genotyping for 9p21 Single Nucleotide Polymorphisms to Predict Risk of Cardiovascular Disease or Aneurysm

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/4:2014
  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.


A number of highly correlated single nucleotide polymorphisms (SNPs) found in the chromosome 9 region p21 locus (9p21) have been significantly associated with myocardial infarction (MI), particularly early onset MI, and other manifestations of cardiovascular disease (CVD). Associations with abdominal aortic aneurysm (AAA) and with intracranial aneurysm have also been reported. Genotyping for 9p21 SNPs may be offered as an approach to identify patients who may be at increased risk of some of these outcomes.


In 2007, genome-wide association studies (GWAS) using SNP arrays resulted in the near simultaneous reporting of the first common genetic variant that affects the risk of coronary heart disease (CHD; defined as inadequate circulation to cardiac muscle and surrounding tissue resulting in MI, unstable angina pectoris, coronary revascularization, or death) in Caucasians.(1-4) The SNPs commonly reported across these studies were supplemented with more SNPs with similar estimates of CHD risk in the same and additional studies. These SNPs were confirmed in case control replication studies in a variety of study populations, showing that the identified SNPs were associated with CHD and even more specifically with MI.(5) All of the SNPs were found within a locus spanning a 58-kilobase region at chromosome 9p21.3 (thus the locus is sometimes represented more specifically as 9p21.3; for simplicity, 9p21 will be used for the rest of this document), are highly correlated (r2>0.8) and thus are said to be in linkage disequilibrium (nonrandom association of alleles). In all studies, the association of any identified SNP with CHD risk was shown to be independent of traditional risk factors.(5)

Several studies have extended the 9p21 association to other vascular diseases including ischemic stroke; thus 9p21 may be reported as associated with CVD outcomes, defined as including CHD outcomes plus ischemic stroke. Associations have also been reported with AAA and with intracranial arterial aneurysm.(6)

Several genes are found at the 9p21 locus, including ANRIL, which encodes a large noncoding RNA that may have regulatory functions, and CDKN2A and CDKN2B, which encode cyclin-dependent kinase inhibitors.(6) The mechanisms by which the SNPs lead to increased CHD risk have been largely unknown. Recently, Harismendy et al identified several potential enhancer regulatory DNA sequences in the 9p21 region.(7) They reported that the SNP rs10747278, consistently associated with increased risk of CHD, occurs in one of these enhancer sequences and that the risk allele disrupts a transcription factor binding site involved in the inflammatory response (STAT1). The interaction of STAT1 with part of the inflammatory signaling pathway, interferon-gamma, is impaired in 9p21 risk carriers. Congrains et al genotyped 18 SNPs across the CVD-associated region and encompassing ANRIL and CDKN2A/B to determine the impact of 9p21 variants on gene expression. (8) The authors reported that “several SNPs in 9p21 locus affect the expression of ANRIL, which is further in control of the regulation of CDKN2A/B and cell growth. Cell proliferation mediates the progression of atherosclerosis and is also directly or indirectly involved in the pathogenesis of diseases associated with this locus.”


The Berkeley HeartLab offers the 9p21 Genotype Test, which detects the rs10757278 A>G and rs1333049 G>C SNPs within the 9p21 locus of chromosome. The information on the website (available online at: indicates that the SNPs have been shown to predict increased risk for early onset MI, for AAA, and for MI/CHD in general. It is suggested that the test may help identify patients at increased risk for these conditions, alerting providers to characterize and reduce other contributing risk factors.

Cardiac risk genotyping panels offered by other laboratories may include and individually report 9p21 SNP results. For example, the deCODE MI™ (deCODe Genetics, Reykjavik) test genotypes 9p21.3 rs10757278 in addition to 7 other SNPs from other chromosomal loci to estimate the risk of CHD and MI.

Regulatory Status

There is no manufactured test kit for 9p21 genotyping that has been reviewed by the U.S. Food and Drug Administration. 9p21 genotyping tests are laboratory-developed tests, offered by clinical laboratories licensed under Clinical Laboratory Improvement Amendment for high-complexity testing.


The use of genotyping for 9p21 single nucleotide polymorphisms (SNPs) is considered investigational, including but not limited to, identification of patients who may be at increased risk of cardiovascular disease or its manifestations (eg, MI, ischemic stroke, peripheral arterial disease, coronary artery calcification), or identification of patients who may be at increased risk for aneurysmal disease (AAAs, intracranial aneurysms, polypoidal choroidal vasculopathy).

Policy Guidelines

There is no specific CPT code for this test. Effective in 2013, if the specific analyte is listed in codes 81200-81355 or 81400-81408, that CPT code would be reported along with the unlisted code 81479 for the analytes that are not listed. If none of the analytes are listed in the more specific CPT codes, unlisted code 81479 would be reported for the whole test.

Prior to 2013, a series of molecular diagnostic codes (83890-83912) or an unlisted code such as 84999 (unlisted chemistry procedure) would likely have been used.

An example of a possible series of CPT codes used prior to 2013 for this test would be:


83892 x 4

83896 x 4

83898 x 2

83903 x 2


Benefit Application
BlueCard/National Account Issues

None identified. 


This policy was created in May 2011 and updated periodically with literature review. The most recent literature review was performed through February 27, 2014.

Literature Review

Analytic Validity

In the case of 9p21 mutations, analytic validity refers to a test’s technical accuracy in detecting a mutation that is present or in excluding a mutation that is absent. Limited information is available on the analytic validity of the available 9p21 genotyping methods. The deCODE MI test is based on the Centaurus™ Assay (Nanogen Inc., San Diego, CA), which is a real-time polymerase chain reaction (PCR)‒based assay that uses fluorescence detection of PCR products by spectrometry.(3) Published literature describing the development of the Centaurus Assay reported 100% concordance with a criterion standard.(9) Real-time PCR-based methods are generally considered to have high accuracy.

Clinical Validity

9p21 polymorphisms have been associated with multiple types of cardiovascular disease (CVD). The strength of association between the polymorphisms and each disease type (ie, clinical validity) is discussed separately.

9p21 Polymorphisms and Coronary Heart Disease

Meta-analyses. Palomaki et al conducted the first formal systematic review of the 9p21 literature to estimate the strength of the association between established 9p21 single nucleotide polymorphism (SNP) variants and coronary heart disease (CHD) and to examine clinical utility.(10) This review was commissioned by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG). Sixteen published studies that analyzed 47 data sets and that reported 9p21 SNP genotypes in association with outcomes of CHD (including myocardial infarction [MI]) or coronary artery disease (CAD; the result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium, and the most common cause of CHD) were included in this review. Ischemic stroke and aneurysm outcomes were excluded from this analysis; all CHD/CAD outcomes were combined. Data sets were limited to Asian and white populations.

Three publications were cohort studies, the rest case control studies (level 1 and level 2 evidence, respectively, using EWG methods).(11) Five SNPs in the 9p21 locus (rs1333049, rs10757274, rs2383207, rs2891168, and rs10757278) covered all studies/data sets. First, the review demonstrated that the choice of SNP was relatively unimportant; in combining the data from 2 studies, 4 SNPs provided nearly identical odds ratios (ORs). Thus, the results from only 1 SNP per study were used.

Across all studies, consensus genotype frequencies in controls were 27%, 50%, and 23% for 0, 1, and 2 at-risk alleles, respectively. The random-effects summary OR across all studies/data sets was 1.25 (95% confidence interval [CI], 1.21 to 1.29; p<0.001; I2=10%) for subjects with 2 at-risk SNP alleles compared with subjects with 1 at-risk allele. When the same analysis was restricted to individuals younger than 55 years of age, the summary OR increased to 1.35 (95% CI, 1.3 to 1.4). Limiting the data sets to only those with upper age cutoff levels greater than 70 years, the summary OR was 1.19 (95% CI, 1.13 to 1.25; p<0.001). For subjects (all data sets) with no at-risk alleles compared with subjects with 1 at-risk allele, the summary OR was 0.80 (95% CI, 0.77 to 0.82; p<0.001). No differences were found between Asians and whites.

Since this study, several additional meta-analyses of 9p21 genotyping have been published. Schunkert et al and the CARDIOGRAM Consortium conducted a meta-analysis of 14 genome-wide association studies of CAD.(12) The 9p21 association per risk allele with CAD, as measured by SNP rs4977574, was 1.29 (95% CI, 1.23 to 1.36; p=1.35´10−22). In an earlier report of this analysis, the association was stronger among cases younger than 50 years of age at an OR of 1.45 (p<0.001).(13) The Coronary Artery Disease Genetics Consortium meta-analyzed 4 large GWASs of CAD and reported an allele risk of 1.20 (95% CI, 1.16 to 1.25; p=1.62´10−25) for 9p21 SNP rs4977574 and CAD.(14) These results compare well with Palomaki et al.(10)

Zhou et al conducted a meta-analysis of 7 case control studies (N=7123 total) and found associations between early-onset CAD and rs2383207 (OR=0.79; 95% CI, 0.71 to 0.88; p<0.001), rs10757278 (OR=1.28; 95% CI, 1.15 to 1.42; p<0.001), rs10757274 (OR=1.17; 95% CI, 1.08 to 1.33; p=0.02), and rs2383206 (OR=1.17; 95% CI, 1.10 to 1.25; p<0.001).(15) In a meta-analysis of 21 studies that included patients with information on CAD, MI status and 9p21 genotype (N=33,673), Chan et al also found associations with CAD and the 9p21 locus and reported an OR of 1.15 (95% CI, 1.04 to 1.26) for heterozygous carriers and an OR of 1.23 (95% CI, 1.08 to 1.39) for homozygous carriers. However, when underlying CAD was present in both case subjects (n=17,791) and control subjects (n=15,882), the prevalence of MI was not significantly associated with the 9p21 risk allele (OR=0.99; 95% CI, 0.95 to 1.03).(16) In a meta-analysis of 21 case control studies evaluating the association between 9p21 SNPs and CHD in an east Asian population, including 25,945 cases and 31,777 controls, Dong et al found a significant association between the allele rs1333049 and CHD (OR=1.30; 95% CI, 1.25 to 1.35; p<0.001).(17)

Individual Studies: 9p21 polymorphisms and CHD/CAD. Several studies analyzing individual patient cohorts or case control populations for association of 9p21 and CHD/CAD have been published since the Palomaki et al review.(5,18-26) Most results again compare well with Palomaki et al. Scheffold et al(5) evaluated a population of male patients with acute MI compared with an otherwise comparable population of males without an event and reported a slightly higher allele risk for several 9p21 SNPs (approximate OR range, 1.6-1.9). The estimates increased when the population was limited to those cases with a family history of MI (approximate OR range, 1.9-2.8); the authors point out that the combination risk factor of family history plus 9p21 status is similar in value to those of traditional risk factors such as hypertension, diabetes mellitus, and current smoking.

Beckie et al studied the allelic frequencies and haplotype structure of genetic variants on chromosome 9p21 in a cohort of black and white women with early onset CHD.(23,24) The authors report interethnic diversity in the SNP risk alleles and the haplotype structure of chromosome 9p21 SNP variants, suggesting that different variants may influence CHD in whites and blacks. Shiffman also reported no association of rs10757274 and incident MI in African American men (n=228) and women (n=405) aged 65.2 or older.(26)

Wang et al studied CAD in a Chinese Han cohort with and without type 2 diabetes.(27) An adjusted (gender, hypertension, hyperlipidemia, smoking) analysis of the homozygous risk genotype for rs1333049 showed an increased risk of early-onset CAD among diabetic patients (OR=2.367; 95% CI, 1.258 to 4.453; p=0.008), but not among nondiabetic patients (OR=1.632; 95% CI, 0.995 to 2.654, p=0.057).

Individual Studies: 9p21 Allele Dosage and Disease Severity, Progression, and Risk of Death. Dandona et al reported a strong direct association between the proportion of early onset patients with angiographically determined 3-vessel disease and increasing gene dosage of 9p21 SNP rs1333049 (per risk allele copy OR=1.45; 95% CI, 1.18 to 1.79; p=4.26x10-4).(20) Patel et al also reported greater 9p21 risk allele frequency with increasing angiographically defined CAD severity (p=0.003).(21) In a case control study with a 10-year follow-up of cases (n=1508), Ardissino et al reported that rs1333040 was significantly associated with coronary atherosclerosis progression (heterozygous hazard ratio [HR], 1.5; 95% CI, 1.17 to 2.02; homozygous HR=2.2; 95% CI, 1.3 to 2.7).(28) There was no significant association with cardiovascular death or the recurrence of MI.

In a retrospective analysis of a cohort of 589 patients who underwent percutaneous coronary intervention for ST-elevation MI, Szpacowicz et al evaluated the association of the 9p21 SNPs rs1333049, rs10757278, and rs4977574 with 5-year all-cause mortality.(29) In the cohort as a whole, there was no significant association between genotype and mortality. However, among the subgroup of 238 patients with high risk of death at 6 months post admission (GRACE risk score ≥155), heterozygotes and high-risk homozygotes had significantly higher 5-year mortality than low-risk homozygotes (32.4% vs 12.3%, p=0.008, adjusted for Bonferroni correction).

9p21 Polymorphisms and Ischemic Stroke

Several studies have reported, with mixed results, on the association of 9p21 with ischemic stroke, an outcome not included in the studies discussed in the prior text. Anderson et al conducted a meta-analysis of 8 studies, focusing on 2 9p21 SNPs, s1537378 and rs10757278.(30) Inclusion of all data resulted in a high degree of heterogeneity; restriction to only those studies with sufficient information to allow stroke subtype-specific analysis (n=5) resulted in an overall OR estimate of 1.15 (95% CI, 1.08 to 1.23; p<0.001), and a large artery subtype estimate from 3 cohorts of 1.20 (95% CI, 1.08 to 1.33; p<0.001), suggesting that the risk is largely restricted to the large artery subtype. In a meta-analysis by Traylor et al of 15 studies that included 12,389 subjects with ischemic stroke and 62,004 controls, the 9p21 locus was only associated with large-vessel stroke.(31) Olsson et al published a case control study of the association of 9p21 and ischemic stroke in individuals younger than 70 years.(32) In this study, the low-risk allele of 9p21 SNP rs7857345 showed significant association with decreased risk of large vessel disease after adjusting for traditional risk factors (OR=0.58; 95% CI, 0.39 to 0.86). However, not all tested 9p21 SNPs were significant. Dutta et al studied CAD mortality at older ages in association with 9p21 variants, reporting a positive association with mortality but no significant association with deaths due to stroke (HR=1.07; 95% CI, 0.81 to 1.41; p=0.63).(25)

Since the publication of the previous meta-analyses, Chou et al conducted a retrospective analysis of neuropathology and genotyping on 755 deceased participants from 2 longitudinal cohort studies on memory and aging.(33) The authors evaluated the association between macro- and microscopic infarcts on neuropathology and 74 SNPs associated with well-established ischemic stroke risk factors and those previously found to be associated with clinical stroke in GWAS. A 9p21 SNP at the CDKN2A/B locus (rs2383207) was significantly associated with the presence of macroscopic infarct on pathology (OR=1.26; 95% CI, 1.02 to 1.55; p=0.031).

Dichgans et al(34) analyzed data from the CARDIOGRAM/C4D consortium study previously described(12,13) in conjunction with data from the METASTROKE consortium(31) to evaluate whether CAD and ischemic stroke share genetic risk in respect to common genetic variants. The authors found that the 9p21 locus was significantly associated with both CAD and the phenotype of large artery stroke (PLAS=3.85´10-6; Spearman ρ for large artery stroke/CAS, 0.85; p=2.9E-35).

9p21 Polymorphisms and Aneurysms

The 9p21 locus has been associated with risk of both intracranial and abdominal aortic aneurysms. In 2013, Alg et al reported results from a systematic review and meta-analysis of all genetic association studies of sporadic intracranial aneurysm to identify genetic risk factors for intracranial aneurysm.(35) The authors included 66 cohort or case control studies of intracranial aneurysms that examined a total of 41 SNPs, not limited to the 9p21 locus, in 29 genes. Among polymorphisms with the strongest associations with intracranial aneurysm were the 9p21 SNPs rs10757278 (OR=1.29; 95% CI, 1.21 to 1.38) and rs1333040 (OR=1.24; 95% CI, 1.20 to 1.29).

There has been a greater focus on the association of 9p21 with abdominal aortic aneurysm (AAA). Several studies report 9p21 allele-specific estimates of risk in the range of 1.2 to 1.8.(36-40) Biros et al combined the results of their study with the results of previous studies and reported a combined estimate of about 1.3 for both 9p21 SNPs rs10757278 and rs1333049.(39) This is lower than other well-characterized risk factor estimates for AAA such as age (OR=~1.7 per 7 years), family history (OR=~1.9), and smoking (OR=~5).(41)

Association of 9p21 with Other Conditions

A few studies have explored the association of 9p21 variants with a variety of other conditions such as peripheral arterial disease, (42) coronary artery calcification,(43) aortic calcification,(44) polypoidal choroidal vasculopathy (characterized by aneurismal dilations at the border of the choroidal vascular network),(45) and arterial stiffness in hypertensive individuals.(46) In contrast, Folsom et al found no association between SNPs at the 9p21 locus with arterial elasticity and retinal microvascular diameter.(47)

While some studies reported positive associations, the strength of the associations was modest and none suggested clinical use.

Section Summary

The clinical validity of 9p21 with CHD/CAD outcomes is well-established and consistent in multiple independent populations, with evidence of increasing severity of outcomes with increasing risk allele dosage. The magnitude of increased risk is modest, with ORs for CVD generally in the 1 to 2 range. The clinical validity for 9p21 and ischemic stroke or AAA is less well-studied and less certain.

Clinical Utility

Clinical utility is demonstrated when the evidence shows that using a test changes medical management for at least some patients, and these changes lead to improved outcomes. Most of the evidence related to the clinical utility of 9p21 testing is related to its role in risk-stratifying patients for CHD; a smaller body of evidence exists for its utility in other conditions.

Clinical Utility of 9p21 and CHD

Palomaki et al addressed clinical utility with a reclassification analysis, evaluating whether genotyping helped reclassify individuals more accurately than traditional risk factors according to their known outcomes, which was measured by calculating the net reclassification index (NRI) with data from 3 studies/4 data sets.(10) For the 4 data sets, the proportions of cases reclassified by 9p21 genotype after initial classification by traditional risk factors were 0.5%, 0.7%, 2.5%, and -0.1%; of controls, 0.3%, 4.2%, -0.1%, and 0%; corresponding NRIs were 0.8%, 4.9%, 2.5%, and -0.2%; none of the NRIs were statistically significant. In addition, the study showing the largest NRI achieved most of the risk reclassification because of reduced risk in subjects without events, which would have less chance of improving outcomes. Moreover, in 2 individual studies the NRI actually worsened when 9p21 risk alleles were added to algorithms that also included family history as a CAD risk factor.(48,49)

Dutta et al also conducted a reclassification analysis, evaluating risk first with Framingham score, then with 9p21 SNP-determined risk added to the Framingham score.(25) In their cohort of community-dwelling elderly subjects followed for 20 years after DNA collection (n=1095), SNP risk predictors identified an additional 6% (N=5) of the 81 CAD deaths within 10 years in the high-risk group, compared with the 21% (n=17) identified by Framingham score. However, a NRI was not reported for a full evaluation of the results. In a similar analysis, Shiffman et al found that adding a 9p21 SNP risk variant to the Framingham score did not improve the area under the curve (AUC) and that the net number of subjects who were reclassified to more appropriate risk categories was 25 or fewer out of 3651 whites, with a NRI of 0.02 or less (p≥0.4). (26) Adding C-reactive protein and KIF6 (see Policy No. 2.04.67) resulted in a larger number of correctly reclassified white men (n=93, p=0.04), but did not improve risk prediction for white women.

Studies have also used the OR associated with a subject’s 9p21 genotype to modify a risk assessment based on traditional risk factors. For example, based on the results of Palomaki et al,(10) a subject with a 10-year CHD risk of 10% based on traditional risk factors who has 2 9p21 at-risk alleles would have his risk estimate increased to about 14% (10%´1.2´1.2) compared with a subject with no at-risk alleles. Davies et al,(22) however, found that the addition of 9p21 to traditional risk factors was not significant as measured by AUC (0.8013 with traditional risk factors alone vs 0.8044 with traditional risk factors plus 9p21; p=0.097). Other similar attempts to add 9p21 alone as a risk factor have not demonstrated significance in addition to traditional risk factors.(48-50) An improved risk calculation, if shown, would be an intermediate outcome. The expectation is that improved risk assessment might influence patient and provider decisions about preventive interventions and behavioral change. However, as Palomaki et al(10) note, only 37% of U.S. physicians reported regular use of a heart disease risk score,(51) and the evidence that such risk scores translate into net clinical benefits is minimal.(52) Thus, the clinical utility of 9p21 genotyping cannot be assumed even if risk assessment is improved.

Do et al(53) tested several 9p21 SNPs in 3820 cases and 4294 matched controls from the multiethnic INTERHEART study of risk factors for acute nonfatal MI, and also collected dietary information. As expected, the SNPs were significantly associated with MI with ORs of approximately 1.2. An analysis of interactions found no significant effect of physical activity or smoking, but a significant interaction with the prudent diet (ie, raw vegetables, fruits, green leafy vegetables, nuts, desserts, dairy products) score, the most significant interaction being with raw vegetable intake. A second, similar analysis in the prospective FINRISK study, a series of population-based CVD risk factor surveys conducted every 5 years in Finland, found a similar interaction with diet and additionally found that the effect was diminished in the high prudent diet consumption group. Thus, the risk effect of the SNP variants may be most pronounced when diet is poor. Although not yet direct evidence of clinical utility, the results suggest the modification of low-level genetic risk with diet.

Gransbo et al evaluated the incremental impact of a 9p21 SNP (rs497757) on CVD risk prediction.(54) The authors used data from the Malmo Diet and Cancer study, a prospective, population-based cohort study that included 28,449 subjects, with the primary outcome of incident CVD. NRI was calculated when the presence of the rs4977574 SNP was added to a prediction model that used traditional risk factors (age, sex, hypertension, lipid-lowering therapy, diabetes, smoking, body mass index). While there was a significant association between the rs4977574 SNP and incident CVD, the addition of the 9p21 genotype did little to improve risk prediction in additive multivariate models. Although statistically significant, the NRI was small (1.2%, p=0.043).

Clinical Utility of 9p21 and Other CVD

Downing et al evaluated the impact of adding 9p21 polymorphism (rs10757269) in a risk-factor-based model predicting peripheral artery disease.(55) Among 393 subjects in the prospective Genetic Determinants of Peripheral Artery Disease study who met study inclusion criteria, the rs10757269 allele was associated with the presence of peripheral artery disease (defined as ankle–brachial index <0.9) after controlling for traditional cardiovascular risk factors and other biomarkers (OR=1.92; 95% CI, 1.29 to 2.85). The addition of 9p21 genotype to a previously-validated peripheral artery disease risk model (including age, sex, race, smoking history, body mass index, hypertension stage, diabetes status, history of CVD, heart failure, CAD) lead to improved risk classification (NRI=33.5%, p=0.001).

Section Summary

The clinical utility of 9p21 mutation testing has not been established. The contribution of 9p21 to overall cardiovascular risk, above that of traditional risk factors, is small and not likely to be clinically important. Studies of risk reclassification do not report that 9p21 testing results in substantial numbers of patients being reclassified to clinically relevant categories.

Ongoing Clinical Trials

A search of the online registry on February 27, 2014, with the term “9p21” identified 2 studies related to the role of 9p21 polymorphisms in CVD :

  • GENErating Behavior Change, An Integrative Health Coaching and Genetic Risk Testing Pilot (NCT01766271). This is a feasibility study that randomizes patients with at least 1 cardiovascular risk factor to standard risk assessment, or standard risk assessment with health coaching, genetic testing or 9p21, or both. Enrollment is planned for 40 subjects; the planned study completion date was June 2013.
  • Diet Intervention and Genetic Study (DIGEST-Pilot) (NCT01658137). This is an open-label pilot study that randomizes healthy adults to a “prudent” or a “typical Western” diet to assess the impact on gene expression measuring ANRIL production. Enrollment is planned for 80 subjects; the planned study completion date was July 2013.


A number of highly correlated single nucleotide polymorphisms (SNPs) found in the chromosome 9 region p21 locus (9p21) have been associated with coronary artery/heart disease (CAD/CHD), intracranial aneurysms, and abdominal aortic aneurysms (AAA). Genotyping for 9p21 SNPs may identify patients who are at increased risk for these conditions or their manifestations.

The association of 9p21 SNP alleles with CAD/CHD outcomes (clinical validity) is well-established and consistent in multiple independent populations, with evidence of increasing severity of outcomes with increasing risk allele dosage. The clinical validity for 9p21 and ischemic stroke or AAA is less well-studied and less certain. Despite the clinical validity evidence for CAD/CHD outcomes, clinical utility has not been established. No studies have shown that 9p21 genotyping significantly improves risk reclassification after initial classification by traditional risk factors, nor have studies shown that the addition of 9p21 genotyping to traditional risk factors improves risk assessment. Thus, 9p21 genotyping for all applications is investigational.

Practice Guidelines and Position Statements

The EGAPP Working Group Published a Recommendation on “genomic profiling to assess cardiovascular risk to improve cardiovascular health,” which included a recommendation on 9p21 profiling alone based on Palomaki et al.(10) In general, the EWG found “… insufficient evidence to recommend testing for the 9p21 genetic variant or 57 other variants in 28 genes . . . to assess risk for cardiovascular disease (CVD) in the general population, specifically heart disease and stroke. The EWG found that the magnitude of net health benefit from use of any of these tests alone or in combination is negligible. The EWG discourages clinical use unless further evidence supports improved clinical outcomes. Based on the available evidence, the overall certainty of net health benefit is deemed “Low.” (56)

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.


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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-PCS (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.


Genomic profiling, cardiovascular disease risk
Genotyping, coronary artery disease risk

Policy History

Date Action Reason
05/12/11 New Policy. Add to Medicine section, Pathology/Laboratory subsection Policy created with literature search through April 2011; considered investigational
5/10/12 Replace policy Policy updated with literature search, references 8, 19-24, 32-34, 40 added. Identification of patients at risk for aneurysmal disease added to policy statement and title, and additional cardiovascular disease added to policy statement (peripheral vascular disease, coronary artery calcification, polypoidal choroidal vasculopathy). All indications remain investigational.
04/11/13 Replace policy Policy updated with literature search through February 2013, references 14-15 and 28 added. All indications remain investigational.
4/10/14 Replace policy Policy updated with literature review through February 27, 2014; references 9, 17, 29, 33-35, 44, 46-47, and 54-55 added. Editorial changes made to rationale. Policy statements unchanged.