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A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

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posted on 16.04.2021, 11:26 by Bianca Berghuis, Caragh Stapleton, Anja C M Sonsma, Janic Hulst, Gerrit-Jan de Haan, Dick Lindhout, Rita Demurtas, EpiPGX Consortium, Roland Krause, Chantal Depondt, Wolfram S Kunz, Federico Zara, Pasquale Striano, John Craig, Pauls Auce, Anthony G Marson, Hreinn Stefansson, Terence J O'Brien, Michael R Johnson, Graeme J Sills, Stefan Wolking, Holger Lerche, Sanjay M Sisodiya, Josemir W Sander, Gianpiero Cavalleri, Bobby PC Koeleman, Mark McCormack

Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy.

Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum.

Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found.

Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

Funding

Dr. Marvin Weil Epilepsy Research Fund

Irish Research Council for Science, Engineering and Technology

UK Department of Health's Biomedical Research Centre

H2020 Marie Skłodowska-Curie Actions, Grant/Award Number: 751761

Punchestown Kidney Research Fund, Grant/Award Number: EPSPG2015

Science Foundation Ireland, Grant/Award Number: 13/CDA/2223

Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie

Epilepsy Society

History

Comments

The original article is available at https://onlinelibrary.wiley.com

Published Citation

Berghuis B, Stapleton C, Sonsma ACM, Hulst J, de Haan GJ, Lindhout D, Demurtas R; EpiPGX Consortium, Krause R, Depondt C, Kunz WS, Zara F, Striano P, Craig J, Auce P, Marson AG, Stefansson H, O'Brien TJ, Johnson MR, Sills GJ, Wolking S, Lerche H, Sisodiya SM, Sander JW, Cavalleri GL, Koeleman BPC, McCormack M. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine. Epilepsia Open. 2019;4(1):102-109.

Publication Date

23 December 2018

PubMed ID

30868120

Department/Unit

  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders

Publisher

Wiley

Version

  • Published Version (Version of Record)