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

Zulfan Zazuli, Corine de Jong, Wei Xu, Susanne J H Vijverberg, Rosalinde Masereeuw, Devalben Patel, Maryam Mirshams, Khaleeq Khan, Dangxiao Cheng, Bayardo Ordonez-Perez, Shaohui Huang, Anna Spreafico, Aaron R Hansen, David P Goldstein, John R de Almeida, Scott V Bratman, Andrew Hope, Jennifer J Knox, Rebecca K S Wong, Gail E Darling, Abhijat Kitchlu, Simone W A van Haarlem, Femke van der Meer, Anne S R van Lindert, Alexandra Ten Heuvel, Jan Brouwer, Colin J D Ross, Bruce C Carleton, Toine C G Egberts, Gerarda J M Herder, Vera H M Deneer, Anke H Maitland-van der Zee, Geoffrey Liu

Published: November 2021


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.

Full Access Link: Journal of Personalized Medicine