Contribution of Genome-Wide Polygenic Score to Risk of Coronary Artery Disease in Childhood Cancer Survivors

BACKGROUND: Adverse cardiovascular outcomes such as coronary artery disease (CAD) are the leading noncancer causes of morbidity and mortality among childhood cancer survivors. OBJECTIVES: The aim of this study was to assess the role of a genome-wide polygenic score (GPS) for CAD, well validated in the general population, and its interplay with cancer-related risk factors among childhood cancer survivors. METHODS: In a cohort study of 2,472 5-year childhood cancer survivors from the St. Jude Lifetime Cohort, the association between the GPS and the risk of CAD was performed using Cox regression models adjusted for age at cancer diagnosis, sex, cumulative dose of anthracyclines, and mean heart radiation dose. RESULTS: Among survivors of European ancestry, the GPS was significantly associated with the risk of CAD (HR per 1 SD of the GPS: 1.25; 95% CI: 1.04-1.49; P = 0.014). Compared with the first tertile, survivors in the upper tertile had a greater risk of CAD (1.51-fold higher HR of CAD [95% CI: 0.96-2.37; P = 0.074]), although the difference was not statistically significant. The GPS-CAD association was stronger among survivors diagnosed with cancer at age <10 years exposed to >25 Gy heart radiation (HR top vs. bottom tertile of GPS: 15.49; 95% CI: 5.24-45.52; P(trend) = 0.005) but not among those diagnosed at age ≥10 years (P(trend) ≥ 0.77) and not among those diagnosed at age <10 years exposed to ≤25 Gy heart radiation (P(trend) = 0.23). Among high-risk survivors, defined by an estimated relative hazard ≥3.0 from fitted Cox models including clinical risk factors alone, the cumulative incidence of CAD at 40 years from diagnosis was 29% (95% CI: 13%-45%). After incorporating the GPS into the model, the cumulative incidence increased to 48% (95% CI: 26%-69%). CONCLUSIONS: Childhood cancer survivors are at risk for premature CAD. A GPS may help identify those who may benefit from targeted screening and personalized preventive interventions.