Polygenic risk score-assessment of drug induced hepatotoxicity in high-risk acute lymphoblastic leukemia

Abstract

Abstract Introduction: Genetic variations are associated with an increasing risk of asparaginase hepatotoxicity in acute lymphoblastic leukemia (ALL). The polygenetic risk assessment (PRS) of the representative genetic variants can contribute to increasing risk prediction to personalize the treatment. Herein, we estimated the single variants-phenotype and polygenetic-phenotype analysis. Materials and methods: A total of 216 high-risk group acute lymphoblastic leukemia patients that have undergone remission induction therapy were recruited. The asparaginase hepatotoxicity assessment was based on serum characteristics and the presence of hepatomegaly. Genotyping was performed and genotype-phenotype associations were further evaluated to include four genetic contrast models (co-dominant, recessive, dominant and over-dominant) and polygenetic risk score. Results:Our results demonstrated that SOD2 rs4880, PNPLA3 rs738409 and ABCC1 rs4148350 allele frequency had significantly protective impact whereas the ABCG2rs2231142 variant has risk causing impact with the hepatotoxicity as compared to the non-hepatotoxicity group. The genetic contrast analysis showed that SOD2rs4880 and PNPLA3 rs738409 variants were significantly associated with a recessive model, ABCC1 rs4148350 variant with the dominant model, ABCG2rs2231142 variant have shown no significant association with hepatotoxicity. The polygenetic risk score assessment demonstrated that the cumulative impact of a higher number of variants (4-8) has higher polygenic risk scores among the hepatotoxicity group. The receiver operating curve (ROC) demonstrated that the area under the ROC curve does not show statistical significance (p=0.07, CI= 0.26-0.49), suggesting the absence of bias in the analysis. Conclusions: In conclusion, our PRS was strongly associated with asparaginase hepatotoxicity in ALL. The PRS provide means to identify those individuals at greater risk of hepatotoxicity and this information will contribute to personalizing treatment in the future