Genetic Variants in SLC22A17 and SLC22A7 are Associated With Anthracycline-Induced Cardiotoxicity in Children

Abstract

Aim: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. Patients & methods: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. Results: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). Conclusion: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

Keywords::

• anthracyclines
• association study
• cardiotoxicity
• childhood cancer
• pharmacogenomics

The Canadian Pharmacogenomics Network for Drug Safety Consortium

The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) Consortium (participants are arranged geographically by institutions across Canada): Vancouver - BC Children’s Hospital, Child & Family Research Institute, CMMT, POPi: Michael Hayden, Bruce Carleton, Colin Ross, Stuart MacLeod, Wyeth Wasserman, Craig Mitton, Anne Smith, Claudette Hildebrand; Lucila Castro Pastrana, Reza Ghannadan, Rod Rassekh, Fudan Miao, Henk Visscher, Michelle Higginson, Adrienne Borrie, Ursula Amstutz, Amit Bhavsar. Calgary - Alberta Children’s Hospital: Cheri Nijssen-Jordan, David Johnson, Linda Verbeek, Rick Kaczowka. Edmonton - Stollery Children’s Hospital: Paul Grundy, Kent Stobart, Bev Wilson, Sunil Desai, Maria Spavor, Linda Churcher, Terence Chow. Winnipeg – Winnipeg Children’s Hospital: Kevin Hall, Nick Honcharik, Sara Israels, Shanna Chan, Byron Garnham, Michelle Staub. London – London Health Sciences Centre: Michael Rieder, Becky Malkin. Hamilton - McMaster Children’s Hospital: Carol Portwine, Amy Cranston. Toronto – Hospital for Sick Children: Gideon Koren, Shinya Ito, Paul Nathan, Mark Greenberg, Facundo Garcia Bournissen, Miho Inoue, Sachi Sakaguchi, Toshihiro Tanaka, Hisaki Fujii, Mina Ogawa, Ryoko Ingram, Taro Kamiya, Smita Karande. Kingston – Kingston General Hospital: Mariana Silva, Stephanie Willing. Ottawa - Children’s Hospital of Eastern Ontario: Régis Vaillancourt, Pat Elliott-Miller, Donna Johnston, Herpreet Mankoo, Elaine Wong, Brenda Wilson, Lauren O’Connor. Ottawa - Health Canada: Maurica Maher. Montreal - Hospital Sainte-Justine: Jean-Francois Bussières, Denis Lebel, Pierre Barret, Aurélie Closon. Montreal - Montreal Heart Institute: Michael Phillips. Montreal – McGill University Health Centre-Montreal Children’s Hospital: Nada Jabado, Anelise Espirito Santo, Martine Nagy. Halifax - IWK Health Centre: Margaret Murray, Darlene Boliver, Marilyn Tiller, Carol-anne Osborne. St. John’s - Janeway Children’s Hospital: Lisa Goodyear, Jack Hand (deceased), Lynette Bowes, Norma Kean.

Author contributions

H Visscher, CJ Ross, SR Rassekh, BC Carleton and MR Hayden designed the research. H Visscher, CJ Ross, SR Rassekh, GS Sandor, EC van Dalen, LC Kremer and HJ van der Pal, performed the research. H Visscher and CJ Ross analyzed data. CJ Ross, HN Caron, PC Ro, BC Carleton and MR Hayden contributed new reagents/analytical tools. H Visscher, CJ Ross, SR Rassekh, GS Sandor, HN Caron, EC van Dalen, LC Kremer, HJ van der Pal, PC Rogers, MJ Rieder, BC Carleton and MR Hayden wrote the manuscript.

Acknowledgements

The authors especially want to thank the study participants and their families for their participation in the CPNDS project and this specific study. The authors also want to acknowledge the support of the CPNDS active ADR surveillance network as well as J van Gelder and RC Heinen for their support in identifying patients in the Dutch-EKZ cohort. The authors thank S Butland for help with bioinformatics analyses.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Financial & competing interests disclosure

This work was supported by the Canadian Institutes of Health Research, Canada Foundation for Innovation, Genome Canada; Genome British Columbia; Genome Quebec; additional funding was provided by Child & Family Research Institute (Vancouver, BC, Canada); Faculties of Pharmaceutical Sciences and Medicine, University of British Columbia; University of Western Ontario; Canada Gene Cure Foundation; Canadian Society of Clinical Pharmacology; C17 Research Network and Childhood Cancer Foundation-Candlelighters Canada; Canadian Paediatric Society, Merck Frosst; Janssen-Ortho; Illumina; Eli Lilly; and Pfizer. This work was funded as part of the peer-reviewed Genome Canada Applied Health Research Program, Canada Foundation for Innovation/Canadian Institutes of Health Research Regional/National Clinical Research Initiatives and Genome British Columbia Translational Program for Applied Health. H Visscher was supported by a postdoctoral research fellowship award from the Michael Smith Foundation for Health Research and the Child & Family Research Institute. The EKZ-AMC Late Effects Study Group is supported by a structural grant from the Stichting Kindergeneeskundig Kankeronderzoek (Foundation for Pediatric Cancer Research). The authors are inventors on patent applications that relate to genetic polymorphisms predictive of anthracycline-induced cardiotoxicity. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by the Canadian Institutes of Health Research, Canada Foundation for Innovation, Genome Canada; Genome British Columbia; Genome Quebec; additional funding was provided by Child & Family Research Institute (Vancouver, BC, Canada); Faculties of Pharmaceutical Sciences and Medicine, University of British Columbia; University of Western Ontario; Canada Gene Cure Foundation; Canadian Society of Clinical Pharmacology; C17 Research Network and Childhood Cancer Foundation-Candlelighters Canada; Canadian Paediatric Society, Merck Frosst; Janssen-Ortho; Illumina; Eli Lilly; and Pfizer. This work was funded as part of the peer-reviewed Genome Canada Applied Health Research Program, Canada Foundation for Innovation/Canadian Institutes of Health Research Regional/National Clinical Research Initiatives and Genome British Columbia Translational Program for Applied Health. H Visscher was supported by a postdoctoral research fellowship award from the Michael Smith Foundation for Health Research and the Child & Family Research Institute. The EKZ-AMC Late Effects Study Group is supported by a structural grant from the Stichting Kindergeneeskundig Kankeronderzoek (Foundation for Pediatric Cancer Research). The authors are inventors on patent applications that relate to genetic polymorphisms predictive of anthracycline-induced cardiotoxicity. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.