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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; Ptrend = 0.005) but not among those diagnosed at age ≥10 years (Ptrend ≥ 0.77) and not among those diagnosed at age <10 years exposed to ≤25 Gy heart radiation (Ptrend = 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.

L ong-term survivors of childhood cancer are at risk for various treatment-related late effects including coronary artery disease (CAD).
Compared with the general population, survivors have more than a 10-fold higher risk of developing CAD 1 that is strongly associated with exposure to chest or mediastinal radiation. [2][3][4] In a study from the St. Jude Lifetime Cohort (SJLIFE), survivors treated with cardiac radiation exposure >15 Gy were at a significantly higher risk for CAD (OR: 10.5; 95% CI: 4.2-26.3) compared with unexposed survivors. 2 CAD was observed in 3.8% of cardiotoxic-exposed survivors and 10.5% of those $40 years of age. Similar findings have also been noted in the Childhood Cancer Survivor Study with radiation exposure to the heart increasing the risk of myocardial infarction in a dose-dependent manner. 4,5 However, the role of anthracyclines in the development of CAD is less clear. Prior studies have shown evidence of vascular inflammation, early atherogenesis, and dyslipidemia in survivors exposed to anthracyclines 6 and suggested a potential indirect association through alteration of brachial artery reactivity 7 and impaired endothelial relaxation, 8 but these associations are not firmly established.
In the general population, both heritable and lifestyle risk factors are known to contribute to the risk of CAD. Estimates of heritability range from 40% to 50%, and genome-wide association studies have identified more than 160 genetic variants affecting the risk of CAD. 9 Individually, these variants contribute a small proportion to the overall risk, but together, in the form of a polygenic score, they can stratify the population by heritable CAD risk. The use of polygenic scores enhances the ability to predict the development of CAD. 10 Khera et al 11 used novel approaches to generate polygenic scores that considered genomewide common variation and showed improved predictive performance compared with traditional polygenic scores that involve only genome-wide significant variants. Their genome-wide polygenic score (GPS) using approximately 6.63 million common genetic variants identified 8% of the population at >3-fold increased risk for CAD. Notably, the prevalence of this GPS-defined high-risk group was 20-fold higher than the carrier frequency of rare monogenic mutations conferring the comparable risk, implying a greater clinical and public health impact. The GPS for CAD risk, initially developed, validated, and tested in the general population of European ancestry from the UK Biobank, has now been validated in independent populations of French Canadian 12 Figure 1). GENETIC DATA. Genotype data were obtained using paired-end whole genome sequencing with approximately 30Â coverage using the HiSeq X10 (Illumina) and/or NovaSeq (Illumina) sequencers. Details of the whole genome sequencing, data processing, and quality control measures are provided elsewhere. [16][17][18] Principal components were generated based on the genotype data of an independent set of common variants using EIGENSTRAT in PLINK version 1.9 19 and used to control for potential population stratification. The nongenetic (clinical risk factors alone) baseline model for CAD risk was fit first adjusting for age at cancer diagnosis (<10 vs $10 years), sex, cumulative anthracycline dose (none, 1-250 mg/m 2 , and >250 mg/ m 2 ), average heart radiation dose (#25 Gy vs >25 Gy), and the top 5 principal components to adjust for a finescale population structure within individuals of European ancestry. 24, 25 The cumulative anthracycline dose was converted to a categoric variable using the cutpoints in the previously published studies. 26,27 Exposure to higher doses of average heart radiation and younger age at diagnosis are known risk factors for CAD in childhood cancer survivors. 2 To assess the GPS-CAD association with respect to these high-risk survivors, age at cancer diagnosis and the average heart radiation dose were also categorized. The median age at diagnosis among survivors with CAD in this study population was 9.8 years; thus, 10 years was chosen as a cutpoint. Exposure to chest radiation is the strongest risk factor for CAD among childhood cancer survivors, which was first recognized among survivors of Hodgkin lymphoma. 28

RESULTS
There  Among survivors diagnosed <10 years of age and exposed to >25 Gy of average heart radiation dose, the   survivors of childhood cancer, a GPS for CAD is predictive of CAD incidence, specifically among those diagnosed with cancer before 10 years of age and exposed to >25 Gy heart radiation.
TRANSLATIONAL OUTLOOK: Future studies should consider incorporating the polygenic risk score with treatment exposures to identify at-risk survivors for CAD who may benefit from targeted screening and personalized preventive interventions.