Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study
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 discove...
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2021
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oai:doaj.org-article:7373dee5fa83488bb27f8905750962c72021-11-25T18:08:13ZAssociation between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study10.3390/jpm111112332075-4426https://doaj.org/article/7373dee5fa83488bb27f8905750962c72021-11-01T00:00:00Zhttps://www.mdpi.com/2075-4426/11/11/1233https://doaj.org/toc/2075-4426This 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 (<i>n</i> = 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 <i>BACH2</i> 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, <i>p</i> = 3.9 × 10<sup>−8</sup>) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, <i>p</i> = 7.4 × 10<sup>−7</sup>) 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 <i>BACH2</i> (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.Zulfan ZazuliCorine de JongWei XuSusanne J. H. VijverbergRosalinde MasereeuwDevalben PatelMaryam MirshamsKhaleeq KhanDangxiao ChengBayardo Ordonez-PerezShaohui HuangAnna SpreaficoAaron R. HansenDavid P. GoldsteinJohn R. de AlmeidaScott V. BratmanAndrew HopeJennifer J. KnoxRebecca K. S. WongGail E. DarlingAbhijat KitchluSimone W. A. van HaarlemFemke van der MeerAnne S. R. van LindertAlexandra ten HeuvelJan BrouwerColin J. D. RossBruce C. CarletonToine C. G. EgbertsGerarda J. M. HerderVera H. M. DeneerAnke H. Maitland-van der ZeeGeoffrey LiuMDPI AGarticlepharmacogenomicscisplatinnephrotoxicitykidney injurygenetic polymorphismsgenome-wide association studyMedicineRENJournal of Personalized Medicine, Vol 11, Iss 1233, p 1233 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
pharmacogenomics cisplatin nephrotoxicity kidney injury genetic polymorphisms genome-wide association study Medicine R |
| spellingShingle |
pharmacogenomics cisplatin nephrotoxicity kidney injury genetic polymorphisms genome-wide association study Medicine R 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 Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study |
| description |
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 (<i>n</i> = 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 <i>BACH2</i> 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, <i>p</i> = 3.9 × 10<sup>−8</sup>) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, <i>p</i> = 7.4 × 10<sup>−7</sup>) 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 <i>BACH2</i> (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Zulfan Zazuli |
| title |
Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study |
| title_short |
Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study |
| title_full |
Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study |
| title_fullStr |
Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study |
| title_full_unstemmed |
Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study |
| title_sort |
association between genetic variants and cisplatin-induced nephrotoxicity: a genome-wide approach and validation study |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/7373dee5fa83488bb27f8905750962c7 |
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