A genetic risk score is associated with incident cardiovascular disease and coronary artery calcium: the Framingham Heart Study

Abstract

Background: Limited data exist regarding the use of a genetic risk score (GRS) for predicting risk of incident cardiovascular disease (CVD) in US-based samples.

Methods and results: By using findings from recent genome-wide association studies, we constructed GRSs composed of 13 genetic variants associated with myocardial infarction or other manifestations of coronary heart disease (CHD) and 102 genetic variants associated with CHD or its major risk factors. We also updated the 13 single-nucleotide polymorphism (SNP) GRSs with 16 SNPs recently discovered by genome-wide association studies. We estimated the association, discrimination, and risk reclassification of each GRS for incident cardiovascular events and prevalent coronary artery calcium (CAC). In analyses adjusted for age, sex, CVD risk factors, and parental history of CVD, the 13 SNP GRSs were significantly associated with incident hard CHD (hazard ratio, 1.07; 95% CI, 1.00-1.15; P=0.04), CVD (hazard ratio per allele, 1.05; 95% CI, 1.01-1.09; P=0.03), and high CAC (defined as >75(th) age- and sex-specific percentile; odds ratio per allele, 1.18; 95% CI, 1.11-1.26; P=3.4×10(-7)). The GRS did not improve discrimination for incident CHD or CVD but led to modest improvements in risk reclassification. However, significant improvements in discrimination and risk reclassification were observed for the prediction of high CAC. The addition of 16 newly discovered SNPs to the 13 SNP GRSs did not significantly modify these results.

Conclusions: A GRS composed of 13 SNPs associated with coronary disease is an independent predictor of cardiovascular events and of high CAC, modestly improves risk reclassification for incident CHD, and significantly improves discrimination for high CAC. The addition of recently discovered SNPs did not significantly improve the performance of this GRS.

Figure 1. Fully Adjusted Odds Ratios for High CAC in Offspring Participants Included in the Incident Events Analysis (A) and in Generation 3 Participants (B)

Several major discoveries in the genetics of cardiovascular disease have been made in recent years. However, whether the addition of genetic information can improve current risk prediction models for cardiovascular disease (e.g. Framingham Risk Score) has not been well established. Using data from over 3,000 individuals from the Framingham Offspring Study, we demonstrate that a genetic risk score made up of 13 genetic variants associated with myocardial infarction is associated with both incident coronary heart disease and cardiovascular disease. Furthermore, we also show that the genetic risk score is also associated with high coronary artery calcium, a subclinical marker of atherosclerosis. However, the addition of these genetic variants only led to very modest improvements to risk assessment when added to the Framingham Risk Score. Our results suggest that the addition of currently available genetic information does not appreciably improve the assessment of future cardiovascular risk at the current time. As additional genetic variants are discovered, future iterations of a genetic risk score will require further investigation.