Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study
Zazuli, Zulfan; de Jong, Corine; Xu, Wei; Vijverberg, Susanne J H; Masereeuw, Rosalinde; Patel, Devalben; Mirshams, Maryam; Khan, Khaleeq; Cheng, Dangxiao; Ordonez-Perez, Bayardo; Huang, Shaohui; Spreafico, Anna; Hansen, Aaron R; Goldstein, David P; de Almeida, John R; Bratman, Scott V; Hope, Andrew; Knox, Jennifer J; Wong, Rebecca K S; Darling, Gail E; Kitchlu, Abhijat; van Haarlem, Simone W A; van der Meer, Femke; van Lindert, Anne S R; Ten Heuvel, Alexandra; Brouwer, Jan; Ross, Colin J D; Carleton, Bruce C; Egberts, Toine C G; Herder, Gerarda J M; Deneer, Vera H M; Maitland-van der Zee, Anke H; Liu, Geoffrey
(2021) Journal of Personalized Medicine, volume 11, issue 11, pp. 1 - 19
(Article)
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
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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.
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Keywords: Cisplatin, Genetic polymorphisms, Genome-wide association study, Kidney injury, Nephrotoxicity, Pharmacogenomics, Platinum, Medicine (miscellaneous)
ISSN: 2075-4426
Publisher: MDPI Multidisciplinary Digital Publishing Institute
Note: Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
(Peer reviewed)