Genome-wide association study of tyrosine kinase inhibitor–induced hepatotoxicity in All of Us.

Abstract

e15130 Background: Tyrosine kinase inhibitors (TKIs) are widely used as standard therapies for a variety of malignancies; however, clinically significant hepatotoxicity has been frequently reported in patients receiving these agents. Such adverse effects may necessitate treatment interruption or dose modification, thereby imposing a substantial clinical burden. This study aimed to investigate genetic susceptibility to TKI-induced hepatotoxicity by analyzing genetic polymorphisms in patients treated with TKIs. Methods: In this study, a cohort of patients treated with tyrosine kinase inhibitors (TKIs) was constructed using data from the All of Us Research Program. Hepatotoxicity was defined as grade ≥2 liver function abnormalities according to the Common Terminology Criteria for Adverse Events (CTCAE). To identify genetic variants associated with TKI-induced hepatotoxicity, a genome-wide association study (GWAS) was performed. Given the limited sample size, a suggestive significance threshold of P < 1 × 10⁻⁵ was applied. Based on the variants identified in the GWAS, additional multivariable logistic regression analyses and polygenic risk score (PRS) analyses were conducted. Results: Among 811 participants exposed to TKIs, 98 developed grade ≥2 hepatotoxicity, while 713 served as controls. Genome-wide association analysis identified several loci exceeding the suggestive significance threshold (P < 1 × 10⁻⁵), with the strongest association observed at rs72734306 on chromosome 1. Additional suggestive associations were detected at loci near genes involved in immune regulation and endoplasmic reticulum stress–related pathways. In multivariable logistic regression analyses adjusting for age, sex, and concomitant chemotherapy use, several GWAS-identified variants remained significantly associated with TKI-induced hepatotoxicity, whereas clinical covariates were not independently associated with the outcome. Polygenic risk score (PRS) analysis showed a trend toward an increased risk of hepatotoxicity with higher PRS values; however, this association did not reach conventional statistical significance (P = 0.051). Conclusions: These research findings may help predict liver toxicity side effects in patients using TKIs and contribute to personalized treatment.