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ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children

Abstract

Respiratory depression (RD) is a serious side effect of morphine and detrimental to effective analgesia. We reported that variants of the ATP binding cassette gene ABCC3 (facilitates hepatic morphine metabolite efflux) affect morphine metabolite clearance. In this study of 316 children undergoing tonsillectomy, we found significant association between ABCC3 variants and RD leading to prolonged postoperative care unit stay (prolonged RD). Allele A at rs4148412 and allele G at rs729923 caused a 2.36 (95% CI=1.28–4.37, P=0.0061) and 3.7 (95% CI 1.47–9.09, P=0.0050) times increase in odds of prolonged RD, respectively. These clinical associations were supported by increased formation clearance of morphine glucuronides in children with rs4148412 AA and rs4973665 CC genotypes in this cohort, as well as an independent spine surgical cohort of 67 adolescents. This is the first study to report association of ABCC3 variants with opioid-related RD, and morphine metabolite formation (in two independent surgical cohorts).

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Acknowledgements

This work was supported in part by USPHS Grant #UL1 RR026314 from the National Center for Research Resources and Electronic Medical Records and Genomics (eMERGE) network U01 grant #U01HG006828, NIH and with the Place Outcomes Research Award (PI: SS) and Translational Research Award (PIs: SS), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. The study in the spine surgical cohort was supported by Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under award number K23HD082782 (PI: VC), and the Clinical Research Feasibility Funds (PI: VC) via Grant 8 UL1 TR000077 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. It was also supported by the APSF/ASA Safety Scientist Career Development Award by the Anesthesia Patient Safety Foundation (PI: Chidambaran). Additional research funding support was provided by the Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. No financial support except departmental salary support for the authors. This pharmacogenetic study was designed and undertaken by the authors.

Author contributions

The authors directed and had access to all the analyses and the full clinical and genetic database, wrote all drafts of the report, decided to publish the results and attest for the accuracy and completeness of the data. Specifically, SS, VC and TF conceived of and designed the research. SS, VC, RV, JN and TM acquired the data. SS, VC, RV, AAV, XZ and LJM analyzed and interpreted the data. XZ and JM did localization of SNPs in ABCC3 transporter and proposed mechanistic pathways. XZ and LJM did statistical analyses. VC, RV and SS drafted the initial manuscript. SS participated in funding and supervision. All authors made critical revisions to the report for important intellectual content.

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Correspondence to S Sadhasivam.

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Chidambaran, V., Venkatasubramanian, R., Zhang, X. et al. ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children. Pharmacogenomics J 17, 162–169 (2017). https://doi.org/10.1038/tpj.2015.98

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