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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
Created with literature search/5:2013
  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 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 using single nucleotide polymorphism (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 myocardial infarction [MI], unstable angina pectoris, coronary revascularization, or death) in Caucasians. (1-4) The SNPs reported commonly 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 (the non-random 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 abdominal aortic aneurysm 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-EarlyMICheck™ 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 abdominal aortic aneurysm, and for myocardial infarction / coronary heart disease 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™ test genotypes 9p21.3 rs10757278 in addition to 7 other SNPs from other chromosomal loci to estimate the risk of coronary heart disease 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 (FDA). 9p21 genotyping tests are laboratory-developed tests (LTD), offered by clinical laboratories licensed under Clinical Laboratory Improvement Amendment (CLIA) for high-complexity testing.



The use of genotyping for 9p21 single nucleotide polymorphisms is considered investigational, including but not limited to, identification of patients who may be at increased risk of cardiovascular disease or its manifestations (e.g., MI, ischemic stroke, peripheral arterial disease, coronary artery calcification), or identification of patients who may be at increased risk for aneurysmal disease (abdominal aortic aneurysms, 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 update covers the period from May 2012 through February 2013.

Literature Review

Clinical Validity

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. (9) 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. (10) 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 one 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]: 1.21-1.29; p<0.001; I2=10%) for individuals with 2 at-risk SNP alleles compared to individuals with one 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: 1.3-1.4). Limiting the data sets to only those with upper age cutoff levels greater than 70 years, the summary OR was 1.19 (95% CI: 1.13-1.25; p<0.001). For individuals (all data sets) with no at-risk alleles compared to individuals with one at-risk allele, the summary OR was 0.80 (95% CI: 0.77-0.82; 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. (11) The 9p21 association per risk allele with CAD, as measured by SNP rs4977574, was 1.29 (95% CI: 1.23–1.36; p=1.35 × 10−22). In an earlier report of this analysis, the association was stronger among cases less than 50 years of age at an OR of 1.45 (p=0.0015). (12) The Coronary Artery Disease Genetics Consortium meta-analyzed 4 large genome-wide association studies of coronary artery disease (CAD) and reported an allele risk of 1.20 (95% CI: 1.16–1.25; p=1.62 × 10−25) for 9p21 SNP rs4977574 and CAD. (13) These results compare well with Palomaki et al. (9)

Zhou et al. conducted a meta-analysis of 7 case-control studies (n=7,123 total) and found associations between early-onset CAD and rs2383207 (OR: 0.79, 95% CI: 0.71-0.88, p<0.0001), rs10757278 (OR: 1.28, 95% CI: 1.15-1.42, p<0.00001), rs10757274 (OR: 1.17, 95% CI: 1.08-1.33, p=0.02), and rs2383206 (OR: 1.17, 95% CI: 1.10-1.25, p<0.00001). (14) 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). (15)

Individual Studies. Several studies analyzing individual patient cohorts or case-control populations for association of 9p21 and coronary heart disease (CHD)/CAD have been published since the Palomaki et al. review. (5, 16-24) Most results again compare well with Palomaki et al. Scheffold et al. (5) evaluated a population of male patients with acute MI compared to an otherwise comparable population of males without an event and reported a slightly higher allele risk for several 9p21 SNPs (odds ratio, OR: approximate range, 1.6-1.9). The estimates increased when the population was limited to those cases with a family history of MI (OR: approximate 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. (21, 22) 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. (24)

Wang et al. studied CAD in a Chinese Han cohort with and without type 2 diabetes. (25) 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: 1.258–4.453, p=0.008), but not among non-diabetic patients (OR: 1.632, 95% CI: 0.995–2.654, p=0.057).

9p21 Allele Dosage and Disease Severity, Progression. 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 (OR: per risk allele copy, 1.45, 95% CI: 1.18-1.79; p=4.26x10-4). (18) Patel et al. also reported greater 9p21 risk allele frequency with increasing angiographically-defined CAD severity (p=0.003). (19) In a case-control study with a 10-year follow-up of cases (n=1,508), 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) and homozygous HR: 2.2 (95% CI: 1.3 to 2.7). (26) There was no significant association with cardiovascular death or the recurrence of MI.

9p21 Association with 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 two 9p21 SNPs, s1537378 and rs10757278. (27) 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=0.0001), and a large artery subtype estimate from 3 cohorts of 1.20 (95% CI: 1.08 to 1.33, p=0.0006), 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 individuals with ischemic stroke and 62,004 controls, the 9p21 locus was only associated with large-vessel stroke. (28) Olsson et al. published a case-control study of the association of 9p21 and ischemic stroke in individuals younger than 70 years. (29) 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: 0.39–0.86). 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: 0.81–1.41; p=0.63). (23)

9p21 Association with Aneurysm. The 9p21 locus has been associated, along with 4 other genetic markers, with risk for intracranial aneurysm. However, these risk factors explain only up to 5% of the familial risk, reducing enthusiasm for genetic testing for this outcome at this time. 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 1.2-1.8. (30-33) 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. (33) 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). (34)

9p21 Association with Other Conditions. A few studies have explored the association of 9p21 variants with a variety of other conditions such as peripheral arterial disease, (35) coronary artery calcification, (36) and polypoidal choroidal vasculopathy (characterized by aneurismal dilations at the border of the choroidal vascular network). (37) While all studies reported positive associations, the strength of the associations was modest and none suggested clinical use.

Conclusions. 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 odds ratios for cardiovascular disease generally in the 1-2 range. The clinical validity for 9p21 and ischemic stroke or AAA is less well-studied and less certain.

Clinical Utility

Clinical utility is satisfied when the evidence shows that using a test to change medical management for at least some patients significantly improves outcomes. Palomaki et al. addressed clinical utility with a reclassification analysis, asking whether or not 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. (9) 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 individuals 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. (38, 39)

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. (23) In their cohort of community-dwelling elderly people followed for 20 years after DNA collection (n=1,095), SNP risk predictors identified an additional 6% (N=5) of the 81 CAD deaths within 10 years in the high-risk group, compared to the 21% (n=17) identified by Framingham score. However, a net reclassification index 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 individuals who were reclassified to more appropriate risk categories was 25 or fewer out of 3,651 whites, with a net reclassification index <0.02 (p>0.4). (24) Adding C-reactive protein and KIF6 (see Medical Reference Policy 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 an individual’s 9p21 genotype to modify a risk assessment based on traditional risk factors. For example, based on the results of Palomaki et al., (9) an individual with a 10-year CHD risk of 10% based on traditional risk factors who has two 9p21 at-risk alleles would have their risk estimate increased to about 14% (10% x 1.2 x.1.2) compared to an individual with no at-risk alleles. Davies et al., (20) 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 versus 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. (38-40) 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. (9) note, only 37% of U.S. physicians reported regular use of a heart disease risk score, (41) and the evidence that such risk scores translate into net clinical benefits is minimal. (42) Thus, the clinical utility of 9p21 genotyping cannot be assumed even if risk assessment is improved.

Do et al. (43) tested several 9p21 SNPs in 3,820 cases and 4,294 matched controls from the multiethnic INTERHEART study of risk factors for acute non-fatal 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 (i.e., raw vegetables, fruits, green leafy vegetables, nuts, desserts, and 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 cardiovascular disease (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.

Conclusions. 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 online registry in March 2013 identified 2 small pilot randomized trials addressing 9p21 genetic risk information. The impact of incorporating 9p21 genetic risk information into coronary heart disease counseling will be evaluated in NCT01766271. In NCT01658137, investigators will examine whether a high fruit and vegetable diet will interact with the 9p21 risk allele to alter the risk of myocardial infarction.


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. 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 abdominal aortic aneurysm 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 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. (9) 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.” (44)

Medicare National Coverage



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  43. Do R, Xie C, Zhang X et al. The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study. PLoS Med 2011; 8(10):e1001106.
  44. Recommendations from the EGAPP Working Group: genomic profiling to assess cardiovascular risk to improve cardiovascular health. Genet Med 2010; 12(12):839-43.







No specific code (See Policy Guidelines)

ICD-9-CM diagnosis


Investigational for all relevant diagnoses

ICD-10-CM (effective 10/1/14)   Investigational for all relevant diagnoses
ICD-10-PCS (effective 10/1/14)   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.