What are the implications of a positive 9p21 test on cardiovascular disease risk and management?

Implications of a Positive 9p21 Test on Cardiovascular Disease Risk and Management

Testing for the 9p21 genetic variant is not recommended for cardiovascular disease risk assessment as it provides negligible clinical benefit and should not guide patient management decisions. 1

Clinical Validity of 9p21 Testing

• The 9p21 variant shows the strongest and most reproducible association with heart disease among all studied genetic variants, with a per-allele odds ratio between 1.2-1.3 (or up to 1.56 in some analyses) 1
• The variant occurs in approximately 75% of the population (except African Americans) and is associated with a 25% increased risk for coronary artery disease (CAD) with one copy and 50% increased risk with two copies 2
• Homozygous carriers (about 21% of the population) have an estimated risk of myocardial infarction 1.64 times greater than non-carriers, with early-onset cases having 2.02 times greater risk 3
• The 9p21 association with heart disease is independent of all traditional risk factors, suggesting it operates through currently unknown pathogenic mechanisms 2, 1

Limited Clinical Utility

• Despite its association with heart disease, adding 9p21 testing to traditional risk factors provides only minimal improvement in risk prediction 1
• The net reclassification index (measuring improvement in risk prediction) when adding 9p21 to traditional risk factors ranges from -0.2% to 4.9%, which is statistically insignificant or clinically unimportant 1
• No studies have formally evaluated the clinical utility of 9p21 testing or other cardiogenomic profiles 1
• There is no direct evidence available to assess the health benefits or harms of adding 9p21 markers to traditional risk factors 1

Risk Stratification Impact

• The 9p21 variant's greatest influence on risk stratification occurs in the intermediate-risk categories (5-20% 10-year CHD risk), where approximately 12% of individuals may be reclassified 4
• However, this modest reclassification does not translate to clear guidance on how to modify patient care to improve outcomes 1
• For patients with established coronary heart disease, 9p21 testing shows no significant association with subsequent coronary events (odds ratio 1.02,95% CI 0.99-1.05), suggesting it has limited value for secondary prevention 5

Management Implications

• The Evaluation of Genomic Applications in Practice and Prevention Working Group (EWG) discourages clinical use of 9p21 testing unless further evidence supports improved clinical outcomes 1
• Physicians should continue to rely on well-established recommendations for cardiac risk assessment (smoking, blood pressure, and lipid screening) 1
• All patients should receive consistent counseling regarding appropriate physical activity and nutrition behaviors to reduce cardiac risk, regardless of 9p21 status 1
• There is currently no specific treatment approach based on 9p21 status that has been shown to improve outcomes 2

Common Pitfalls and Caveats

• Patients may request 9p21 testing or present with results from direct-to-consumer genetic tests 1
• A positive 9p21 test result might create anxiety without providing actionable clinical information 1
• There is a risk of false reassurance for those with negative results who may still have significant cardiovascular risk from traditional factors 1
• The 9p21 variant may promote atheroma development (as suggested by its association with subsequent revascularization procedures), but this mechanism has not translated to improved risk prediction for acute events 5

In conclusion, while 9p21 has a clear association with coronary heart disease risk, current evidence does not support its use in clinical practice for risk assessment or management decisions. Traditional risk factors remain the cornerstone of cardiovascular risk assessment and management.