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Outcome definition influences the relationship between genetic polymorphisms of ERCC1, ERCC2, SLC22A2 and cisplatin nephrotoxicity in adult testicular cancer patients
Zazuli Z., Otten L.S., Drogemoller B.I., Medeiros M., Monzon J.G., Wright G.E.B., Kollmannsberger C.K., Bedard P.L., Chen Z., Gelmon K.A., McGoldrick N., Kitchlu A., Vijverberg S.J.H., Masereeuw R., Ross C.J.D., Liu G., Carleton B.C., Maitland-van der Zee A.H.
[vc_row][vc_column][vc_row_inner][vc_column_inner][vc_separator css=”.vc_custom_1624529070653{padding-top: 30px !important;padding-bottom: 30px !important;}”][/vc_column_inner][/vc_row_inner][vc_row_inner layout=”boxed”][vc_column_inner width=”3/4″ css=”.vc_custom_1624695412187{border-right-width: 1px !important;border-right-color: #dddddd !important;border-right-style: solid !important;border-radius: 1px !important;}”][vc_empty_space][megatron_heading title=”Abstract” size=”size-sm” text_align=”text-left”][vc_column_text]© 2019 by the authors. Licensee MDPI, Basel, Switzerland.Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009-2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI:0.08-0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI:1.96-9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI:1.69-15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.[/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="Author keywords" size="size-sm" text_align="text-left"][vc_column_text][/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="Indexed keywords" size="size-sm" text_align="text-left"][vc_column_text]Cisplatin,Genetic polymorphisms,Kidney injury,Nephrotoxicity,Pharmacogenetics[/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="Funding details" size="size-sm" text_align="text-left"][vc_column_text]Funding: This research was funded by the Canadian Foundation for Innovation/Canadian Institutes of Health Research (CIHR) (grant number CIHR CRI-88362), the CIHR-Drug Safety and Effectiveness Network (grants number CIHR TD1 137714 and CIHR TD2 117588), Genome BC and Genome Canada (grant number 272PGX), the BC Children’s Hospital Research Institute Bertram Hoffmeister Postdoctoral Fellowship Award (B.I.D), Michael Smith Foundation for Health Research Scholar Program (C.J.D.R) and 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 APC was funded by Indonesia Endowment Fund for Education (LPDP).[/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="DOI" size="size-sm" text_align="text-left"][vc_column_text]https://doi.org/10.3390/genes10050364[/vc_column_text][/vc_column_inner][vc_column_inner width=”1/4″][vc_column_text]Widget Plumx[/vc_column_text][/vc_column_inner][/vc_row_inner][/vc_column][/vc_row][vc_row][vc_column][vc_separator css=”.vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}”][/vc_column][/vc_row]