TY - JOUR
T1 - Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity
T2 - A Genome-Wide Approach and Validation Study
AU - Zazuli, Zulfan
AU - de Jong, Corine
AU - Xu, Wei
AU - Vijverberg, Susanne J. H.
AU - Masereeuw, Rosalinde
AU - Patel, Devalben
AU - Mirshams, Maryam
AU - Khan, Khaleeq
AU - Cheng, Dangxiao
AU - Ordonez-Perez, Bayardo
AU - Huang, Shao Hui
AU - Spreafico, Anna
AU - Hansen, Aaron R.
AU - Goldstein, David P.
AU - de Almeida, John R.
AU - Bratman, Scott V.
AU - Hope, Andrew
AU - Knox, Jennifer J.
AU - Wong, Rebecca K. S.
AU - Darling, Gail E.
AU - Kitchlu, Abhijat
AU - van Haarlem, Simone W. A.
AU - van der Meer, Femke
AU - van Lindert, Anne S. R.
AU - Heuvel, Alexandra Ten
AU - Brouwer, Jan
AU - Ross, Colin J. D.
AU - Carleton, Bruce C.
AU - Egberts, Toine C. G.
AU - Herder, Gerarda J. M.
AU - Deneer, Vera H. M.
AU - Maitland-van der Zee, Anke H.
AU - Liu, Geoffrey
N1 - Funding Information: Funding: This research was funded by US NCI funded CIDR projects in head and neck and esophageal cancer, and the Indonesia Endowment Fund for Education (LPDP) Ministry of Finance, the Republic of Indonesia (as a part of ZZ’s Ph.D. project, grant no. 20161022049506). The Discovery cohort was further funded by the Princess Margaret Cancer Foundation (The Lusi Wong Family Fund, Alan Brown Chair in Molecular Genomics, The Wharton family, Joe’s Team, Gordon Tozer, Bruce Galloway and the Elia family; and The Princess Margaret Hospital Head and Neck Cancer Translational Research Program). The PGxLUNG study was funded by the St Antonius Onderzoeksfonds and patient funding. Financial support for the genotyping was provided by Roche Nederland B.V. The funding sources had no role in study design, data collection, data analysis, data interpretation, or the writing of the report. Funding Information: This research was funded by US NCI funded CIDR projects in head and neck and esophageal cancer, and the Indonesia Endowment Fund for Education (LPDP) Ministry of Finance, the Republic of Indonesia (as a part of ZZ?s Ph.D. project, grant no. 20161022049506). The Discovery cohort was further funded by the Princess Margaret Cancer Foundation (The Lusi Wong Family Fund, Alan Brown Chair in Molecular Genomics, The Wharton family, Joe?s Team, Gordon Tozer, Bruce Galloway and the Elia family; and The Princess Margaret Hospital Head and Neck Cancer Translational Research Program). The PGxLUNG study was funded by the St Antonius Onderzoeksfonds and patient funding. Financial support for the genotyping was provided by Roche Nederland B.V. The funding sources had no role in study design, data collection, data analysis, data interpretation, or the writing of the report.We gratefully acknowledge the participation of all patients and families who took part in this study. We also like to thank D.S. Arsyad and L.B. Richards for their help with technical software and analysis suggestions. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - Cisplatin
KW - Genetic polymorphisms
KW - Genome-wide association study
KW - Kidney injury
KW - Nephrotoxicity
KW - Pharmacogenomics
KW - Platinum
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85122850452&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34834585
U2 - https://doi.org/10.3390/JPM11111233
DO - https://doi.org/10.3390/JPM11111233
M3 - Article
C2 - 34834585
SN - 2075-4426
VL - 11
JO - Journal of Personalized Medicine
JF - Journal of Personalized Medicine
IS - 11
M1 - 1233
ER -