Int J Clin Pharm. 2025 Nov 20. doi: 10.1007/s11096-025-02038-3. Online ahead of print.
ABSTRACT
INTRODUCTION: Cisplatin is a cornerstone chemotherapeutic agent frequently associated with dose-limiting ototoxicity. Increasing evidence suggests that immune-mediated mechanisms may influence interindividual susceptibility to this adverse effect; however, the role of inherited immune traits remains poorly understood.
AIM: This study aimed to evaluate the causal relationship between 33 inherited immune traits and cisplatin-induced ototoxicity using Mendelian randomization (MR), and to identify age-stratified susceptibility markers in pediatric and adult cancer survivors.
METHOD: MR was used to assess the causal effects of genetically predicted immune traits on cisplatin-induced ototoxicity. Single-nucleotide polymorphisms associated with immune traits were selected from large-scale genome-wide association study datasets. The primary analysis used the inverse variance weighted method with MR-Egger, weighted median, weighted mode, and MR-PRESSO as the sensitivity approaches. Bidirectional MR and sensitivity analyses were conducted to assess robustness and rule out reverse causation. Bonferroni correction was employed to minimize potential false-positive findings (P < 0.05/165 ≈ 0.0003).
RESULTS: Transforming Growth Factor-beta principal component analysis (TGF-β PCA) showed an age-stratified effect: it was associated with increased risk of hearing loss in pediatric patients (OR (95% CI): 1.0 × 101 (1.6 × 100-6.6 × 101), P = 0.014) but conferred strong protection against Speech Recognition Threshold (SRT) impairment (OR (95% CI): 2.8 × 10⁻1 (1.4 × 10⁻1-5.3 × 10⁻1), P = 0.00012) and hearing loss (OR (95% CI): 4.7 × 10⁻1 (2.7 × 10⁻1-8.1 × 10⁻1), P = 0.006) in adults. Additional protective associations have been identified for T Central Memory (TCM) cells and Programmed Cell Death Protein-1 (PD-1) in adults. Reverse MR analysis excluded significant reverse causation. Following Bonferroni correction, the association between TGF-β PCA and SRT remained statistically significant (P < 0.0003) in the adult cohort. However, all other associations in adults and the entire pediatric cohort demonstrated only nominal significance (0.0003 ≤ P < 0.05).
CONCLUSION: Inherited immune traits, particularly TGF-β PCA, PD-1, and TCM cells, exhibit age-stratified causal effects on cisplatin-induced ototoxicity. These findings suggest the use of immunogenetic profiling for risk prediction and personalized strategies in oncology pharmacy practice.
PMID:41264078 | DOI:10.1007/s11096-025-02038-3
