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DESCRIPTIONA number of highly correlated single nucleotide polymorphisms (SNPs) found in the chromosome 9 region p21 locus (9p21) 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, intracranial aneurysms, and other vascular disorders have also been reported. Genotyping for 9p21 SNPs has been investigated to identify patients at risk of cardiovascular disorders.
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. Additional studies identified other SNPs with similar estimates of CHD risk. 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). 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 (defined as CHD and cerebrovascular disease) outcomes. Associations have also been reported with abdominal aortic aneurysm and with intracranial arterial aneurysm and other vascular diseases.
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 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. 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.”
Commercially Available Tests
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 7 other SNPs from other chromosomal loci to estimate the risk of coronary heart disease and MI.
There is no manufactured test kit for 9p21 genotyping that has been reviewed by the Food and Drug Administration. 9p21 genotyping tests are laboratory-developed tests, offered by clinical laboratories licensed under CLIA for high-complexity testing.
Related medical policies are as follows:
POLICYThe 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).
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
POLICY HISTORY07/21/2011: Approved by Medical Policy Advisory Committee.
07/13/2012: Policy statement updated to add the following indications: peripheral arterial disease, coronary artery calcification). Also changed those who may be at increased risk of abdominal aortic aneurysm or intracranial aneurysm to patients who may be at increased risk for aneurysmal disease (abdominal aortic aneurysms, intracranial aneurysms, polypoidal choroidal vasculopathy). Intent of policy statement unchanged.
08/07/2013: Policy reviewed; no changes to policy statement. Added CPT code 81479 to the Code Reference section.
06/11/2014: Policy reviewed; descripton updated. Added the Novel Lipid Risk Factors and Biomarkers in Risk Assessment and Management of Cardiovascular Disease policy as a related policy in the description section. Policy statement revised to state that 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). Intent of policy statement unchanged.
07/30/2015: Code Reference section updated for ICD-10.
09/11/2015: Policy description updated regarding tests. Policy statement unchanged. Investigative definition updated in the Policy Guidelines section.
06/07/2016: Policy number L.2.04.430 added.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.71
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.