Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

Abstract

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10^-8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10^-7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

Keywords: cisplatin; genetic polymorphisms; genome-wide association study; kidney injury; nephrotoxicity; pharmacogenomics; platinum.

Figure 1

Flowchart of this study. (A) Discovery cohort (n = 608). The discovery cohort consisted of head and neck cancer patients (n = 555) and esophageal cancer patients (n = 167). Three arrays were used for genotyping. After pre-imputation QC, imputation and post-imputation QC, data of 608 patients in total were included for analysis. (B) Validation cohort (n = 149). The validation cohort consisted of non-small-cell lung cancer patients (n = 350). After pre-imputation QC, imputation, post-imputation QC and exclusion for chemotherapeutic therapy, 149 patients in total were included for analysis. Abbreviations: AKI-CTCAE (Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury), GWA (genome-wide association), SNPs (single-nucleotide polymorphisms), and QC (quality control).

Figure 2

Genome-wide meta-analysis results of cisplatin-induced nephrotoxicity using AKI-CTCAE and eGFR phenotypes. (A) Manhattan plot showing logistic regression results using the AKI-CTCAE phenotype; −log10 p-values are plotted against the respective chromosomal position of each SNP. (B) A quantile–quantile (Q–Q) plot showing the distribution of p-values in the GWAS using the AKI-CTCAE phenotype. (C) Manhattan plot showing logistic regression results using the eGFR phenotype. (D) Q–Q plot showing the distribution of p-values in the GWAS using the eGFR phenotype.