1. Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study
- Author
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Zazuli, Zulfan, Jong, Corine de de, Xu, Wei, Vijverberg, Susanne J. H., Masereeuw, Rosalinde, Patel, Devalben, Mirshams, Maryam, Khan, Khaleeq, Cheng, Dangxiao, Ordonez-Perez, Bayardo, Huang, Shao Hui, Spreafico, Anna, Hansen, Aaron R., Goldstein, David P., Almeida, John R. de de, Bratman, Scott V., Hope, Andrew, Knox, Jennifer J., Wong, Rebecca K. S., Darling, Gail E., Kitchlu, Abhijat, Haarlem, Simone W. A. van van, Meer, Femke van der, Lindert, Anne S. R. van, Heuvel, Alexandra ten ten, Brouwer, Jan, Ross, Colin J. D., Carleton, Bruce C., Egberts, Toine C. G., Herder, Gerarda J. M., Deneer, Vera H. M., Zee, Anke H. Maitland-van der, Liu, Geoffrey, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, APH - Personalized Medicine, CCA - Cancer biology and immunology, and Pulmonology
- Subjects
Oncology ,pharmacogenomics ,Candidate gene ,medicine.medical_specialty ,genome-wide association study ,business.industry ,nephrotoxicity ,Medicine (miscellaneous) ,cisplatin ,Single-nucleotide polymorphism ,Genome-wide association study ,Article ,Nephrotoxicity ,Minor allele frequency ,genetic polymorphisms ,Internal medicine ,Cohort ,Genetic predisposition ,kidney injury ,Medicine ,platinum ,Allele ,business - 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.
- Published
- 2021