mp-542 - Medical Policies - Alabama
Genotyping for 9p21 Single Nucleotide Polymorphisms to Predict Risk of Cardiovascular Disease or Aneurysm
Policy Number: MP-542
ARCHIVED – Refer to AIM Genetic Testing Guidelines Effective 3/1/20
Latest Review Date: September 2019
Effective March 28, 2016: Active Policy but no longer scheduled for regular literature reviews and updates.
Genotyping for 9p21 single nucleotide polymorphisms is considered not medically necessary and investigational for all clinical uses including but not limited to identification patients who may be at risk for the following:
- Cardiovascular disease or its manifestations (e.g., MI myocardial infarction, ischemic stroke, PAD peripheral arterial disease, coronary artery calcification), or
- Aneurysmal disease (AAA abdominal aortic aneurysms, intracranial aneurysms, polypoidal choroidal vasculopathy)
A number of highly correlated single nucleotide polymorphisms (SNPs) found at the 9p21 locus have been significantly associated with risk of myocardial infarction (MI), particularly early onset MI, and other manifestations of cardiovascular disease (CVD). Associations between 9p21 SNPs and risk of abdominal aortic aneurysm (AAA), intracranial aneurysms, and other vascular disease have also been reported. Genotyping for 9p21 SNPs has been investigated to identify patients at risk of cardiovascular disorders.
Several laboratories offer 9p21 genotyping. For example, the Berkeley HeartLab (Quest Diagnostics) offers the 9p21 Genotype Test, which detects the rs10757278 A>G and rs1333049 G>C SNPs within the 9p21 locus of chromosome 9. Baylor Miraca Genetics Laboratories offers genotyping of the rs10757278 A>G polymorphism at 9p21.
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 seven other SNPs from other chromosomal loci to estimate the risk of CHD and MI.
This policy is based on literature review most recently performed September 27, 2019.
Summary of Evidence
The association of single nucleotide polymorphisms at the 9p21 locus with coronary artery/heart disease (CAD/CHD) incidence and 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 the association of 9p21 polymorphisms ischemic stroke, aneurysms, or other vascular disorders is less well-studied and less certain. Despite the evidence that 9p21 polymorphisms are associated with CAD/CHD outcomes, the clinical utility of 9p21 genotyping has not been established. Studies have conclusively demonstrated that 9p21 genotyping significantly improves risk reclassification after initial classification by traditional risk factors, or that addition of 9p21 genotyping to traditional risk factors improves risk assessment. No studies were identified that evaluate whether the use of 9p21 genotyping is associated with changes in patient management, improvements in clinical outcomes, or both. There is insufficient evidence to determine if the use of the 9p21 genetic variant predicts clinical events or improves health outcomes, thus, 9p21 genotyping for all applications is investigational.
Practice Guidelines And Position Statements
In 2013, the American College of Cardiology Foundation and the American Heart Association Task Force on Practice Guidelines issued guidelines on the assessment of cardiovascular risk, which did not address assessment of 9p21 polymorphisms.
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. 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.”
U.S. Preventive Services Task Force Recommendations
No recommendations for 9p21 genotyping to identify risk for cardiovascular disease have been identified.
Genotyping, chromosome 9p21, cardiovascular disease risk, aneurysm, EarlyMICheck™ Genotype Test, deCODE MI™, CardioIQ®
APPROVED BY GOVERNING BODIES:
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 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: www.bhlinc.com/clinicians/test-descriptions/9p21) 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™ (deCODe Genetics, Reykjavik) 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.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply.
FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
There is no specific CPT code for this test. If the specific analyte is listed in codes 81161-81355 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.
The Quest website reports that their Cardio IQ® 9p21 Genotype test is reported with code 81479
Unlisted molecular pathology procedure
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- Alg VS, Sofat R, Houlden H et al. Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals. Neurology 2013; 80(23):2154-65.
- American College of Cardiology/American Heart Association.2013 ACC/AHA guideline on the assessment of cardiovascular risk. Retrieved June 2, 2017 from http://www.onlinejacc.org/content/accj/63/25_Part_B/2935.full.pdf?_ga=2.185171625.1411743239.1496427944-2128906682.1496427944.
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- Ardissino D, Berzuini C, Merlini PA et al. Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction. J Am Coll Cardiol 2011; 58(4):426-3
- Beckie TM, Beckstead JW, Groer MW. The association between variants on chromosome 9p21 and inflammatory biomarkers in ethnically diverse women with coronary heart disease: a pilot study. Biol Res Nurs 2011; 13(3):306-19.
- Beckie TM, Groer MW, Beckstead JW. The relationship between polymorphisms on chromosome 9p21 and age of onset of coronary heart disease in black and white women. Genet Test Mol Biomarkers 2011; 15(6):435-42.
- Bendjilali N, Nelson J, Weinsheimer S, et al. Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms. J Neurol Neurosurg Psychiatry. Nov 2014;85(11):1280-1283.
- 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.
- 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.
- 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.
- Cesana F, Nava S, Menni C et al. Does the 9p region affect arterial stiffness? Results from a cohort of hypertensive individuals. Blood Press 2013; 22(5):302-6.
- Chan K, Patel RS, Newcombe P et al. Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis. J Am Coll Cardiol 2013; 61(9):957-70.
- Chou SH, Shulman JM, Keenan BT et al. Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations. Cerebrovasc Dis 2013; 36(3):181-8.
- Congrains A, Kamide K, Oguro R et al. Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis 2012; 220(2):449-55.
- 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.
- 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.
- Dichgans M, Malik R, Konig IR et al. Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke 2014; 45(1):24-36.
- 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.
- Dong L, Wang H, Wang DW et al. Association of chromosome 9p21 genetic variants with risk of coronary heart disease in the East Asian population: a meta-analysis. Ann Hum Genet 2013; 77(3):183-90.
- Downing KP, Nead KT, Kojima Y et al. The combination of 9p3 genotype and biomarker profile improves a peripheral artery disease risk prediction model. Vasc Med 2014; 19(1):3-8.
- Dutta A, Henley W, Lang IA et al. The coronary artery disease-associated 9p21 variant and later life 20-year survival to cohort extinction. Circ Cardiovasc Genet 2011; 4(5):542-8.
- Folsom AR, Pankow JS, Li X et al. No association of 9p21 with arterial elasticity and retinal microvascular findings. Atherosclerosis 2013; 230(2):301-3.
- 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.
- Gransbo K, Almgren P, Sjogren M et al. Chromosome 9p21 genetic variation explains 13% of cardiovascular disease incidence but does not improve risk prediction. J Intern Med 2013; 274(3):233-40.
- Guo, J., Li, W., Wu, Z., Cheng, X., Wang, Y., & Chen, T. (2013). Association between 9p21.3 genomic markers and coronary artery disease in East Asians: a meta-analysis involving 9,813 cases and 10,710 controls. Molecular Biology Reports, 40 (1), 337-343. Abstract retrieved June 2, 2017 from PubMed database.
- 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.
- 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.
- 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.
- Johansen CT, Lanktree MB, Hegele RA. Translating genomic analyses into improved management of coronary artery disease. Future Cardiol 2010; 6(4):507-21.
- Kutyavin IV, Milesi D, Belousov Y et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res 2006; 34(19):e128.
- 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-
- Lian J, Ba Y, Dai D, et al. A replication study and a meta-analysis of the association between the CDKN2A rs1333049 polymorphism and coronary heart disease. J Atheroscler Thromb. 2014; 21(11):1109-1120.
- Matoo,S., Fallah, M., Daneshpour, M., Mousavi, R., Sedaghati, K., Hasanzad,M., & Azizi, F. (2017). Increased risk of CHD in the presence of rs7865618 (A allele): Tehran lipid and glucose study. Archives of Iranian Medicine, 20 (3), 153-157. Abstract retrieved June 2, 2017 from PubMed database.
- 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.
- Murabito JM, White CC, Kavousi M et al. Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. Circ Cardiovasc Genet 2012; 5(1):100-12.
- Ni X, Zhang J. Association between 9p21 genomic markers and ischemic stroke risk: evidence based on 21 studies. PLoS One. 2014; 9(3):e90255.
- O'Donnell CJ, Kavousi M, Smith AV et al. Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction. Circulation 2011; 124(25):2855-64.
- 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.
- Palomaki GE, Melillo S, Bradley LA. Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA 2010; 303(7):648-56.
- Patel, R., Asselbergs, F., Quyyumi, A., Palmer, T., Finan, C., Tragante, V., et al. (2014). Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events. Journal of the American College of Cardiology, 63 (21), 2234-2245.
- 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.
- 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.
- 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.
- Pott, J., Burkhardt, R., Beutner, F., Horn, K., Teren, A., Kirsten, H., et al. (2017). Genome-wide meta-analysis identifies novel loci of plaque burden in carotid artery. Atherosclerosis, 259, 32-40. Abstract retrieved May 29, 2018 from PubMed database.
- 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.
- Recommendations from the EGAPP Working Group: genomic profiling to assess cardiovascular risk to improve cardiovascular health. Genet Med 2010; 12(12):839-43.
- 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.
- Samani NJ, Erdmann J, Hall AS et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007; 357(5):443-53.
- 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.
- 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.
- 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.
- Shiffman D, O'Meara ES, Rowland CM et al. The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study. BMC Cardiovasc Disord 2011; 11:10.
- 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.
- Sturiale CL, Fontanella MM, Gatto I, et al. Association between polymorphisms rs1333040 and rs7865618 of chromosome 9p21 and sporadic brain arteriovenous malformations. Cerebrovasc Dis. 2014; 37(4):290-295.
- Sun, J., & Sun, F. (2017). Analysis on the polymorphism of chromosome region9p21 and the susceptibility of carotid plaque. European Neurology, 77 (1-2), 25-31. (Abstract retrieved May 30, 2019 from PubMed database)
- Szpakowicz A, Kiliszek M, Pepinski W, et al. Polymorphism of 9p21.3 locus is associated with 5-year survival in high-risk patients with myocardial infarction. PLoS One. 2014; 9(8):e104635.
- Szpakowicz A, Pepinski W, Waszkiewicz E et al. Polymorphism of 9p21.3 locus is associated with 5- year survival in high-risk patients with myocardial infarction. PLoS One 2013; 8(9):e72333.
- 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.
- 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.
- 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.
- Traylor M, Farrall M, Holliday EG et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 2012; 11(11):951-
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- Wang W, Peng WH, Lu L et al. Polymorphism on chromosome 9p21.3 contributes to early-onset and severity of coronary artery disease in non-diabetic and type 2 diabetic patients. Chin Med J 2011; 124(1):66-71.
- Wei Y, Xiong J, Zuo S, et al. Association of polymorphisms on chromosome 9p21.3 region with increased susceptibility of abdominal aortic aneurysm in a Chinese Han population. J Vasc Surg. Apr 2014; 59(4):879-885.
- Wei Y, Xiong J, Zuo S et al. Association of polymorphisms on chromosome 9p21.3 region with increased susceptibility of abdominal aortic aneurysm in a Chinese Han population. J Vasc Surg 2013.
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- Zhang X, Wen F, Zuo C et al. Association of genetic variation on chromosome 9p21 with polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. Investig Ophthalmol Vis Sci 2011; 52(11):8063-7.
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Medical Policy Group, April 2011 (1): Update to Policy, Key Points, Key Words and References
Medical Policy Administration Committee, April 2011
Available for comment April 13 – May 30, 2011
Medical Policy Group, May 2011 (1): Update to Policy, Key Points and References
Medical Policy Administration Committee, June 2011
Available for comment June 8 – July 25, 2011
Medical Policy Group, May 2012 (1): Update to Key Points and References; no change to policy statement
Medical Policy Panel, April 2013
Medical Policy Group, April 2013 (1): Update to Descriptions, Key Points, Key Words and References; no change to policy statement, remains investigational; all corresponding tables and informational pages have been updated
Medical Policy Administration Committee, October 2013
Medical Policy Group, January 2014 (1): Creation of individual policy with all references related to 9p21 SNPs removed from medical policy #136; no change to policy statement
Medical Policy Panel, April 2014
Medical Policy Group, April 2014 (1): Update to Key Points and References; no change to policy statement
Medical Policy Panel, April 2015
Medical Policy Group, May 2015 (3): Updates to Description, Key Points, Current Coding, and References; policy statement verbiage updated to include myocardial infarction, no change to intent.
Medical Policy Panel, March 2016
Medical Policy Group, March 2016 (3): Update to Key Words only; no new information available; no change to policy statement; retiring policy
Medical Policy Group, September 2019 (9): Updated Description, Key Points, References. Removed outdated previous coding section. No change to policy statement.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.
The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.
As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:
1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.