In this study, we demonstrated that adding the 9p21 genotype to traditional RF statistically significantly improved CHD risk prediction, with 12–13% of individuals reclassified in the intermediate-low and intermediate-high risk categories of both the ACRS and FRS models. For a large proportion of those reclassified, LDL-C target goals would be altered and thus, therapy recommendations would be changed. We present a simple way to utilize the 9p21 information for calculating the 10-year CHD risk for an individual based on the formula detailed in .
The use of traditional risk factors to predict CHD risk is a well-established clinical tool. The ATP III CHD risk classification is generally accepted by most clinicians as a guideline for both risk prediction and for determining preventive therapy for CHD. Adding certain biomarkers to risk prediction calculations has been shown to modestly improve CHD risk prediction.18, 19
However, in recent years, extensive research has concentrated on associations between genetic markers and CHD.3
In this study, the 9p21 genotype had no association with blood pressure, lipid levels or other traditional RF. A modest association between the GG genotype and a lower BMI was observed in ARIC whites, but this observation has not been replicated in other studies.6
However, the AG/GG genotype’s possible tendency towards a lower BMI would not explain an increased risk for CHD.
The 9p21 variant had a HR of 1.20 per allele (P<3E-06). in ARIC whites, and adding the 9p21 allele to the traditional RF model resulted in a statistically significant improvement of the AROC. In a study by Talmud et al, although the AROC was modestly larger for 10-year risk prediction by adding the 9p21 genotype to traditional RF, it was not statistically significant.6
The statistically significant improvement in the AROC in our study may be related to the larger number of participants (9,998 vs. 2,742) or to the fact that we were examining both men and women vs. men only.6
In the study by Paynter et al, conducted on 22,129 white females, there was no significant improvement in C-statistics in either an ATP III-based risk model or the Reynolds score. The total NRI for the ATP III-based risk score was modestly better (2.7% improvement, P=0.02) after adding the 9p21 allele, and the clinical NRI was not calculated for that model.20
Although the total NRI in our study, which specifically examines correct movement between risk categories, did not show significant improvement between the model with and without the 9p21 allele, the clinical NRI, which examines the intermediate-risk categories in particular, was significantly better for the 9p21 allele model. The clinical NRI results may be useful, because the individuals in the intermediate-risk categories would most benefit from clarifying their risk status by testing “emerging” risk factors, such as the 9p21 allele.
The IDI, which examines improvement in model performance independent of choice of risk categories, was also significantly better for the model with the 9p21 allele. In evaluating the goodness-of-fit, the 9p21 allele + traditional RF model did better than the traditional RF-only model using the Grønnesby-Borgan test. However, both models did not provide a good fit.
The fact that adding the 9p21 allele to the ACRS model had the highest effect on the intermediate-low (~12% reclassified) and intermediate-high (~12% reclassified) risk categories is useful because patients in these “middle” categories are usually the most challenging for clinical evaluation. ATP III guidelines and other guidelines recommend consideration of additional testing, such as imaging and biomarkers, for the >10% to ≤20% 10-year risk group to aid in clinical evaluation and therapeutic strategy.21–23
We suggest that the 9p21 allele genotype may serve as one of these additional modalities.
Although the ATP III guidelines focus on >10% to ≤20% 10-year CHD risk as an intermediate-low risk category, others have expanded this category to either 6–20% or 5–20%.18, 24, 25
In the current study, another consideration for expanding to 5–20% risk category is that the 10-year absolute CHD risk dramatically underestimates the lifetime risk for CHD events. For example, individuals from the intermediate-low category (>5% to ≤10% 10-year risk) who were reclassified to the intermediate-high category (>10% to ≤20% 10-year risk), by adding the 9p21 genotype to the traditional RF model, had an 11.4 CHD event rate per 100 individuals over 10 years of follow up. However, a longer follow up period of 14.6 years in ARIC for the same reclassified population showed a much higher event rate of 19.6 CHD events per 100 individuals. This demonstrated the potential advantage of adding 9p21 testing to traditional RF in defining a group of individuals who would especially benefit from longterm preventive therapy.
In contrast to the intermediate-low and intermediate-high risk groups, the utility of the 9p21 genotype for risk calculation for subjects in the low (0–5% 10-year CHD risk) and high (>20 10-year CHD risk) categories is unclear. In both risk categories, few subjects were reclassified, and for those who were reclassified, no treatment change would seem appropriate.
In summary, we have shown that the 9p21 genotype added to traditional risk factors modestly improved risk classification in the intermediate-low (>5% to ≤10% 10-year CHD risk) and intermediate-high (>10% to ≤20% 10-year CHD risk) categories.. Future studies should be designed to test whether a strategy of altering therapy by virtue of a single SNP or combination of SNP’s could improve clinical outcome.
The 9p21 allele association with CHD events has been shown in multiple cohorts in whites but was not demonstrated in blacks. Thus, the black population of the ARIC study was not included in this analysis. Although there are reports of association between the 9p21 allele and CHD in ethnicities other than whites and blacks, most of these reports include a relatively small number of participants, and further studies are required for verification.26
The ARIC study includes a relatively small number of individuals of ethnicities other than whites and blacks which did not supply enough statistical power to test our hypothesis in these populations. The fact that no other ethnicities other than whites were used for the current analysis, suggests that the results may not be generalized to other populations other than those like the one tested.
Another limitation is the use of a single SNP vs. the use of several SNPs which could have augmented the results of the current analysis. Finally, we did not examine the question of whether the 9p21 allele provided additional information to improve risk assessment if newer biomarkers such as high-sensitivity C-reactive protein, or imaging tests for subclinical atherosclerosis such as carotid intima-media thickness, are included in the multivariate models, and this needs to be addressed in future studies.
In recent years, multiple studies have identified a large number of single nucleotide polymorphisms (SNP’s) associated with coronary heart disease (CHD). Although many of these genetic markers are available commercially, their clinical utility and the appropriate populations for testing are largely unclear. In the current study, we examined the clinical utility of a single SNP in the 9p21 region, which was associated with CHD in multiple studies to address the questions noted above.
Addition of the 9p21 allele to traditional risk factors (RF) modestly improved the 10-year CHD risk prediction in the intermediate risk groups (defined as absolute 10-year CHD risk of 5–20%). Reclassification of an individual from the intermediate risk category to either a lower or higher CHD risk group may influence management base on Adult Treatment Panel (ATP) III guidelines. On the other hand, adding the 9p21 allele to traditional RF for individuals in the low (10-year risk <5%) or high-risk (10-year risk >20%) groups did not demonstrate clinical utility in this study.
In summary, this study demonstrates the clinical utility of adding the 9p21 allele to traditional RF when limited to individuals in the intermediate CHD risk categories. Future studies should be designed to test whether a strategy of altering therapy by virtue of adding a single or combination of SNPs to CHD risk prediction algorithms could improve clinical outcomes.