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.

Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury

“…This study was unable to replicate recently published GWAS findings by Zazuli et al [ 41 ]. Most notably, the study’s main finding, an association between a genetic variant in BACH2 and the cisplatin-induced decrease in eGFR in adult cancer cohorts, was not present in this study’s cohort, although the direction of the effect was the same in both studies.…”

“…Laboratory results were collected from medical records during platinum treatment and at follow-up. For validation purposes, phenotypes were defined in the manner recently reported by the GWAS of Zazuli et al [ 41 ], in which the serum creatinine values were treated as both continuous and categorical variables. For the continuous variable, the estimated glomerular filtration rate (eGFR) was calculated, both at baseline and at the point at which the highest serum creatinine values were achieved during platinum treatment.…”

“…The variants that were reported to be associated to cisplatin-induced AKI more than once, rs316019 in SLC22A2 , rs11615 and rs3212986 in ERCC1 , and rs13181 and rs1799793 in ERCC2 , were included. Furthermore, statistically significantly ( p < 5 × 10 −8 ) and suggestively ( p < 10 −5 ) associated variants from the GWAS by Zazuli et al (2021) were investigated in this study [ 41 ]. This included a total of 244 genetic variants, with 195 variants for the eGFR-coded analysis (including 5 variants that surpassed the genome-wide significance threshold), and 81 variants for CTCAE-graded analysis, with an overlap of 32 variants.…”

“…The most heavily investigated genes have been the DNA repair genes, ERCC1 and ERCC2 , and the transporter gene, SLC22A2 , but the reported association between variants and cisplatin-induced AKI could often not be replicated [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. One recently published genome-wide association study (GWAS), investigating the associations between cisplatin-induced AKI and genetic variants across the whole genome, identified five novel variants in a cohort of adult cancer patients, including a variant in BACH2 that was also statistically significantly associated in a second validation cohort [ 41 ]. For platinum-induced hypomagnesemia, no studies investigating genetic risk factors have been performed to date.…”

Estimation of kidney function for medication dosing in adult patients with chronic kidney disease: a practice update

“…[34][35][36] Furthermore, the activity of kidney drug transporters may be affected by pharmacogenetic differences and drug-drug interactions. 37 For example, inhibition of apical efflux transporters may reduce drug exit from renal tubular cells, leading to accumulation, nephrotoxicity and systemic toxicity. 38 Additionally, some medications have increased clearance via other elimination routes, for example increased transintestinal clearance of ciprofloxacin has been described in severe kidney dysfunction providing an 'extrarenal safety factor', meaning that linear dose adjustments with decreasing GFR would be highly inappropriate.…”