Development of a Dose-Adjusted Polygenic Risk Model for Anthracycline-Induced Cardiotoxicity.

Abstract

Anthracyclines, which are effective chemotherapeutic agents, cause cardiac dysfunction in up to 57% of patients. The cumulative anthracycline dose is a crucial predictor of cardiotoxicity; however, the cumulative dose alone cannot explain all cardiotoxic events. Strongly associated genetic variants in SLC28A3 , UGT1A6 , and RARG contribute to anthracycline-induced cardiotoxicity in pediatric patients and may help identify those most susceptible. This study aimed to examine how these pharmacogenetic effects are modulated by cumulative anthracycline doses in the development of cardiotoxicity. A total of 595 anthracycline-treated children were genotyped and cardiotoxicity cases were identified. A dose-stratified analysis was performed to compare the contributions of SLC28A3 rs7853758, UGT1A6 rs17863783, and RARG rs2229774 variants to the development of cardiotoxicity in low-dose (<150 mg/m 2 cumulative dose) and high-dose (>250 mg/m 2 cumulative dose) patient groups. Logistic regression was used to model the relationships between the cumulative anthracycline dose, genetic variants, and cardiotoxicity in the full cohort. At < 150 mg/m 2 cumulative anthracycline dose, the SLC28A3 protective variant did not reach statistical significance [odds ratio (OR) 0.46 (95% confidence interval (CI) 0.10-1.45), P = 0.23], but it was statistically significant at doses >250 mg/m 2 [OR 0.43 (95% CI 0.22-0.78), P = 0.0093]. Conversely, the UGT1A6 and RARG risk variants were either statistically significant or approaching significance at doses <150 mg/m 2 [OR 7.18 (95% CI 1.78-28.4), P = 0.0045 for UGT1A6 and OR 2.76 (95% CI 0.89-7.63), P = 0.057 for RARG ], but not at doses >250 mg/m 2 [OR 2.91 (95% CI 0.80-11.0), P = 0.10; OR 1.56 (95% CI 0.89-2.75), P = 0.12]. These findings suggest that the SLC28A3 variant imparts more significant protection for patients receiving higher anthracycline doses, whereas the UGT1A6 and RARG risk variants significantly increased the risk of cardiotoxicity at low anthracycline doses.