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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).
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.
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