TY - JOUR
T1 - Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity
T2 - A Genome-Wide Approach and Validation Study
AU - Zazuli, Zulfan
AU - Jong, Corine de de
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 - Almeida, John R. de de
AU - Bratman, Scott V.
AU - Hope, Andrew
AU - Knox, Jennifer J.
AU - Wong, Rebecca K. S.
AU - Darling, Gail E.
AU - Kitchlu, Abhijat
AU - Haarlem, Simone W. A. van van
AU - Meer, Femke van der
AU - Lindert, Anne S. R. van
AU - Heuvel, Alexandra ten 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 - Zee, Anke H. Maitland-van der
AU - Liu, Geoffrey
PY - 2021/11/20
Y1 - 2021/11/20
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 - pharmacogenomics
KW - cisplatin
KW - nephrotoxicity
KW - kidney injury
KW - genetic polymorphisms
KW - genome-wide association study
KW - platinum
U2 - 10.3390/jpm11111233
DO - 10.3390/jpm11111233
M3 - Article
C2 - 34834585
SN - 2075-4426
VL - 11
SP - 1
EP - 19
JO - Journal of Personalized Medicine
JF - Journal of Personalized Medicine
IS - 11
M1 - 1233
ER -