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
Department of Respiratory Medicine, Academic Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia.
J Pers Med. 2021 Nov 20;11(11):1233. doi: 10.3390/jpm11111233.
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 ( = 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 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, = 3.9 × 10) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, = 7.4 × 10) 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 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.
本研究旨在通过调查此前未研究过的遗传风险变异，并进一步检验此前报道的遗传关联，来评估顺铂诱导的肾毒性的遗传风险因素。在加拿大多伦多接受顺铂治疗的成年患者的发现队列中，对遗传估计的欧洲人进行了全基因组研究（GWAS），随后在来自荷兰的验证队列中采用候选基因方法。此外，在发现队列和验证队列中都对先前报道的遗传关联进行了进一步检验。肾毒性的结局通过两种方式进行评估：（i）使用慢性肾脏病流行病学协作公式（CKD-EPI）计算的估计肾小球滤过率（eGFR）降低，以及（ii）根据急性肾损伤不良事件通用术语标准v4.03（AKI-CTCAE）血清肌酐升高。使用四种不同的Illumina芯片进行基因分型。对基因分型前和基因分型后插补的数据应用了标准质量控制。在发现队列（n = 608）中，五个单核苷酸多态性（SNP）达到全基因组显著性。rs4388268（次要等位基因频率 = 0.23）中的A等位基因，是基因的一个内含子变异，在两种定义中均与顺铂诱导的肾毒性风险增加持续相关，对于eGFR降低达到全基因组显著性（β = -8.4，95%CI -11.4--5.4，P = 3.9 × 10），通过AKI-CTCAE达到提示性关联（OR = 3.9，95%CI 2.3 - 6.7，P = 7.4 × 10）。在149名患者的验证队列中，该变异被确定具有相同的效应方向（eGFR：β = -1.5，95%CI -5.3 - 2.4，AKI-CTCAE：OR = 1.7，95%CI 0.8 - 3.5）。在进行多重检验校正后，我们之前发表的候选基因研究结果无法得到证实。基因（rs4388268）的遗传易感性可能在顺铂诱导的肾毒性发生中起重要作用，这为机制理解、个体化治疗和预防策略提供了机会。
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