Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss

Abstract

Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10(-8), hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents.

Trial registration: ClinicalTrials.gov NCT00033211 NCT00085202.

Figure 1. Genome-wide association results of cisplatin-induced ototoxicity

(a) Association of SNP genotype and ototoxicity was evaluated using the Cox regression model for 1,716,999 SNPs in the discovery GWAS of 268 children with brain tumors uniformly treated with cisplatin-containing therapy. P values (-log₁₀ P, y axis) were plotted against respective chromosomal position of each SNP (x axis). Gene symbol was indicated for ACYP2 locus (2p16.2) achieving genome-wide significance threshold (P < 5×10^-8, dashed blue line). (b) and (c) Relationships between genotype at ACYP2 SNP rs1872328 and ototoxicity in the discovery GWAS series (SJMB96 and SJMB03 cohort, b) and replication series (SJYC07 cohort, c), respectively. P value was determined by two-sided time-dependent regression models as described in Online Methods.