BlueCross and BlueShield of Montana Medical Policy/Codes
Genotyping for 9p21 Genetic Polymorphisms to Predict Cardiovascular Disease Risk
Chapter: Genetic Testing
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013

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 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 MI, unstable angina pectoris, coronary revascularization, or death) in Caucasians.  The SNPs reported commonly across these 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.  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.

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.

Several genes are found at the 9p21 locus, including ANRIL, which encodes a large noncoding RNA which may have regulatory functions, and CDKN2A and CDKN2B, which encode cyclin-dependent kinase inhibitors.  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.  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.  Further study of the relationship between these risk variants, 9p21 regulatory elements, the inflammatory response, and atherosclerosis pathogenesis is planned.

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 (LDT), offered by clinical laboratories licensed under CLIA for high-complexity testing.

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 myocardial infarction, 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, allowing 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 seven other SNPs from other chromosomal loci to estimate the risk of coronary heart disease and MI.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.


Blue Cross and Blue Shield of Montana (BCBSMT) considers genotyping for 9p21 single nucleotide polymorphisms experimental, investigational and unproven for all indications including, but not limited to the following

  • Use to identify patients who may be at increased risk of cardiovascular disease or its manifestations (e.g., myocardial infarction [MI], ischemic stroke), or
  • Those who may be at increased risk of abdominal aortic aneurysm (AAA) or intracranial aneurysm.


Meta-analyses of the Association of 9p21 with Coronary Heart Disease/Coronary Artery Disease (CHD/CAD)

Palomaki et al. conducted the first formal systematic review of the 9p21 literature to estimate the strength of the association between established 9p21 SNP variants and heart disease and to examine clinical utility.  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.  Five SNPs in the 9p21 locus (rs1333049, rs10757274, rs2383207, rs2891168, and rs10757278) covered all studies and/or data sets.  First, the review demonstrated that the choice of SNP was relatively unimportant; in combining the data from two studies, four 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 two 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, three 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.  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).  The Coronary Artery Disease Genetics Consortium meta-analyzed four large genome-wide association studies of 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.  These results compare well with Palomaki et al.

Recent Individual Studies

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.  Most results again compare well with Palomaki et al. Scheffold et al. 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 (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.

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).  Patel et al. also reported greater 9p21 risk allele frequency with increasing angiographically-defined CAD severity (p=0.003).

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 eight studies, focusing on 2 of the studies 9p21 SNPs s1537378 and rs10757278.  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 three 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.  Subsequently Olsson et al. published a case-control study of the association of 9p12 and ischemic stroke in individuals aged younger than 70 years.  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.

9p21 Association with Aneurysm

The 9p21 locus has been associated, along with four 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.  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.  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).

Clinical Utility

The information in the prior text addresses primarily clinical validity, or the association between 9p21 and various outcomes of interest.  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 clinical validity for 9p21 and ischemic stroke or AAA is less well-studied and less certain.  Clinical validity provides the clinical basis for a test, but evidence of clinical utility is needed to support clinical use.

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.  For the four 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 two individual studies the NRI actually worsened when 9p21 risk alleles were added to algorithms that also included family history as a CAD risk factor.

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., an individual with a 10-year CHD risk of 10% based on traditional risk factors who has 2- 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., however, found that the addition of 9p21 to traditional risk factors was not significant as measured by area under the curve (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.  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. note, only 37% of U.S. physicians reported regular use of a heart disease risk score, and the evidence that such risk scores translate into net clinical benefits is minimal.  Thus, the clinical utility of 9p21 genotyping cannot be assumed even if risk assessment is improved.

The EGAPP Working Group Published a 2010 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.  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.”


The association of 9p21 SNP alleles with CHD/CAD 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 CHD/CAD outcomes, however, clinical utility, i.e. that the use of the test to change medical management improves CHD/CAD health outcomes, is not 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, an intermediate outcome.  Thus, 9p21 genotyping for all applications is experimental, investigational and unproven.


Disclaimer for coding information on Medical Policies         

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.          

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.         

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes

Investigational, experimental and unproven for all diagnosis codes.

ICD-10 Codes

Investigational, experimental and unproven for all diagnosis codes.

Procedural Codes: 84999
  1. Lederle FA, Johnson GR, Wilson SE et al. The aneurysm detection and management study screening program: validation cohort and final results.  Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators.  Arch Intern Med 2000; 160(10):1425-30.
  2. Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.  Nature 2007; 447(7145):661-78.
  3. McPherson R, Pertsemlidis A, Kavaslar N et al. A common allele on chromosome 9 associated with coronary heart disease.  Science 2007; 316(5830):1488-91.
  4. Helgadottir A, Thorleifsson G, Manolescu A et al.  A common variant on chromosome 9p21 affects the risk of myocardial infarction.  Science 2007; 316(5830):1491-3.
  5. Samani NJ, Erdmann J, Hall AS et al.  Genomewide association analysis of coronary artery disease.  N Engl J Med 2007; 357(5):443-53.
  6. Helgadottir A, Thorleifsson G, Magnusson KP et al.  The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.  Nat Genet 2008; 40(2):217-24.
  7. Bown MJ, Braund PS, Thompson J et al.  Association between the coronary artery disease risk locus on chromosome 9p21.3 and abdominal aortic aneurysm.  Circ Cardiovasc Genet 2008; 1(1):39-42.
  8. Talmud PJ, Cooper JA, Palmen J et al.  Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men.  Clin Chem 2008; 54(3):467-74.
  9. Sheridan SL, Crespo E. Does the routine use of global coronary heart disease risk scores translate into clinical benefits or harms?  A systematic review of the literature.  BMC Health Serv Res 2008; 8:60.
  10. Teutsch SM, Bradley LA, Palomaki GE et al.  The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group.  Genet Med 2009; 11(1):3-14.
  11. Thompson AR, Golledge J, Cooper JA et al.  Sequence variant on 9p21 is associated with the presence of abdominal aortic aneurysm disease but does not have an impact on aneurysmal expansion.  Eur J Hum Genet 2009; 17(3):391-4.
  12. Paynter NP, Chasman DI, Buring JE et al.  Cardiovascular disease risk prediction with and without knowledge of genetic variation at chromosome 9p21.3.  Ann Intern Med 2009; 150(2):65-72.
  13. Brautbar A, Ballantyne CM, Lawson K et al.  Impact of adding a single allele in the 9p21 locus to traditional risk factors on reclassification of coronary heart disease risk and implications for lipid-modifying therapy in the Atherosclerosis Risk in Communities study.  Circ Cardiovasc Genet 2009; 2(3):279-85.
  14. Sposito AC, Ramires JA, Jukema JW et al.  Physicians' attitudes and adherence to use of risk scores for primary prevention of cardiovascular disease: cross-sectional survey in three world regions.  Curr Med Res Opin 2009; 25(5):1171-8.
  15. Johansen CT, Lanktree MB, Hegele RA.  Translating genomic analyses into improved management of coronary artery disease.  Future Cardiol 2010; 6(4):507-21.
  16. Preuss M, Konig IR, Thompson JR et al.  Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: A Genome-wide association meta-analysis involving more than 22 000 cases and 60 000 controls.  Circ Cardiovasc Genet 2010; 3(5):475-83.
  17. Paynter NP, Chasman DI, Pare G et al.  Association between a literature-based genetic risk score and cardiovascular events in women.  JAMA 2010; 303(7):631-7.
  18. Ripatti S, Tikkanen E, Orho-Melander M et al.  A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses.  Lancet 2010; 376(9750):1393-400.
  19. Dandona S, Stewart AF, Chen L et al.  Gene dosage of the common variant 9p21 predicts severity of coronary artery disease.  J Am Coll Cardiol 2010; 56(6):479-86.
  20. Patel RS, Su S, Neeland IJ et al.  The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease.  Eur Heart J 2010; 31(24):3017-23.
  21. Davies RW, Dandona S, Stewart AF et al.  Improved prediction of cardiovascular disease based on a panel of single nucleotide polymorphisms identified through genome-wide association studies.  Circ Cardiovasc Genet 2010; 3(5):468-74.
  22. Anderson CD, Biffi A, Rost NS et al.  Chromosome 9p21 in ischemic stroke: population structure and meta-analysis.  Stroke 2010; 41(6):1123-31.
  23. Biros E, Cooper M, Palmer LJ et al.  Association of an allele on chromosome 9 and abdominal aortic aneurysm.  Atherosclerosis 2010; 212(2):539-42.
  24. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.  Recommendations from the EGAPP Working Group: genomic profiling to assess cardiovascular risk to improve cardiovascular health.  Genet Med 2010; 12(12):839-43.
  25. Palomaki GE, Melillo S, Bradley LA.  Association between 9p21 genomic markers and heart disease: a meta-analysis.  JAMA 2010; 303(7):648-56.
  26. Scheffold T, Kullmann S, Huge A et al.  Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry.  BMC Cardiovasc Disord 2011; 11:9.
  27. Harismendy O, Notani D, Song X et al.  9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response.  Nature 2011; 470(7333):264-8.
  28. Schunkert H, Konig IR, Kathiresan S et al.  Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.  Nat Genet 2011; 43(4):333-8.
  29. Coronary Artery Disease (C4D) Genetics Consortium.  A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease.  Nat Genet 2011; 43(4):339-44.
  30. Olsson S, Jood K, Blomstrand C et al.  Genetic variation on chromosome 9p21 shows association with the ischaemic stroke subtype large-vessel disease in a Swedish sample aged </= 70.   Eur J Neurol 2011; 18(2):365-7.
  31. Genotyping for 9p21 Genetic Polymorphisms to Predict Cardiovascular Disease Risk.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2011 May) Medicine 2.04.71.
September 2013  New 2013 BCBSMT medical policy.  Genotyping for 9p21 single nucleotide polymorphisms is considered experimental, investigational and unproven for all indications.
®Registered marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans. ®LIVE SMART. LIVE HEALTHY. is a registered mark of BCBSMT, an independent licensee of the Blue Cross and Blue Shield Association, serving the residents and businesses of Montana.
CPT codes, descriptions and material only are copyrighted by the American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS Restrictions Apply to Government Use. CPT only © American Medical Association.
Genotyping for 9p21 Genetic Polymorphisms to Predict Cardiovascular Disease Risk