Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults

Abstract

Background: Understanding the predictive utility of previously derived polygenic risk scores (PRSs) for long-term risk of coronary heart disease (CHD) and its additive value beyond traditional risk factors can inform prevention strategies. Methods: Data from adults 20 to 59 years of age who were free of CHD from the FOS (Framingham Offspring Study) and the ARIC (Atherosclerosis Risk in Communities) study were analyzed. Because the PRS was derived from samples of predominantly European ancestry, individuals who self-reported White race were included. The sample was stratified by age and cohort: young (FOS, 20–39 years [median, 30 years] of age), early midlife (FOS, 40–59 years [median, 43] years of age), and late midlife (ARIC, 45–59 years [median, 52 years] of age). Two previously derived and validated prediction tools were applied: (1) a 30-year traditional risk factor score and (2) a genome-wide PRS comprising >6 million genetic variants. Hazard ratios for the association between each risk estimate and incident CHD were calculated. Predicted and observed rates of CHD were compared to assess discrimination for each model individually and together with the optimism-corrected C index (95% CI). Results: Among 9757 participants, both the traditional risk factor score (hazard ratio per 1 SD, 2.60 [95% CI, 2.08–3.27], 2.09 [95% CI, 1.83–2.40], and 2.11 [95% CI, 1.96–2.28]) and the PRS (hazard ratio, 1.98 [95% CI, 1.70–2.30], 1.64 [95% CI, 1.47–1.84], and 1.22 [95% CI, 1.15–1.30]) were significantly associated with incident CHD in young, early midlife, and late midlife, respectively. Discrimination was similar or better for the traditional risk factor score (C index, 0.74 [95% CI, 0.70–0.78], 0.70 [95% CI, 0.67–0.72], and 0.72 [95% CI, 0.70–0.73]) compared with an age- and sex-adjusted PRS (0.73 [95% CI, 0.69–0.78], 0.66 [95% CI, 0.62–0.69], and 0.66 [95% CI, 0.64–0.67]) in young, early-midlife, and late-midlife participants, respectively. The ΔC index when PRS was added to the traditional risk factor score was 0.03 (95% CI, 0.001–0.05), 0.02 (95% CI, −0.002 to 0.037), and 0.002 (95% CI, −0.002 to 0.006) in young, early-midlife, and late-midlife participants, respectively. Conclusions: Despite a statistically significant association between PRS and 30-year risk of CHD, the C statistic improved only marginally with the addition of PRS to the traditional risk factor model among young adults and did not improve among midlife adults. PRS, an immutable factor that cannot be directly intervened on, has minimal clinical utility for long-term CHD prediction when added to a traditional risk factor model.

The necessity of incorporating non-genetic risk factors into polygenic risk score models

“…Although models based on sex, BMI, parental disease and smoking status perform relatively well, there is still added value of the genetic risk scores, albeit limited, in line with earlier reports 27 – 29 , 42 . We observe that when genetic risk is also included on top of sex, BMI, parental disease and smoking status, the incidence odds ratio increases from 4.0 to 5.8 for T2D and from 3.0 to 4.7 for CAD (Fig.…”

“…Visa versa, the added value of PGS was only limited to these existing models. As a result of the established limited added predictive power resulting from adding PGS to existing risk models 27 , 29 , to date they are rarely used in the clinical setting. On the other hand, public interest in genetic risk has increased as evidenced by the billion-dollar companies selling PGS commercially, resulting in more disease risk awareness 8 .…”

Polygenic score informed by genome-wide association studies of multiple ancestries and related traits improves risk prediction for coronary artery disease

“…Additionally, the association between GPS Mult and CAD was stronger in younger individuals ages 40-54 years (OR/SD 2.17, 95%CI 2.04-2.31, p<0.001) and 55-64 years (OR/SD 2.18, 95%CI 2.11-2.25, p<0.001), when compared with older individuals ages 65-75 years (OR/SD 2.08, 95%CI 2.01-2.15, p<0.001), consistent with recent studies (Supplementary Figure 2). 7,[48][49][50] GPS Mult showed stronger association with CAD risk when compared with the previously published GPS 2018 14 in direct comparison using the same group of individuals for validation. Among individuals with CAD, the median percentile of GPS Mult is significantly higher than that of the GPS 2018 , 75 (IQR 50 -91) vs 69 (IQR 43 -88) (Figure 3A).…”

“…[3][4][5][6] As CAD is a heritable disease, leveraging the increasing amount of widely available genetic data offers additional opportunities to significantly enhance CAD risk prediction across all groups early in life, particularly at the extremes of the risk distribution. 7,8 Polygenic scores integrate data from genome-wide association studies into a single quantitative and predictive metric of inherited risk. [9][10][11][12] .…”

“…3–6 As CAD is a heritable disease, leveraging the increasing amount of widely available genetic data offers additional opportunities to significantly enhance CAD risk prediction across all groups early in life, particularly at the extremes of the risk distribution. 7,8…”