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

Bianca Berghuis, Caragh Stapleton, Anja C.M. Sonsma, Janic Hulst, Gerrit Jan de Haan, Dick Lindhout, Rita Demurtas, 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 & 7 others Holger Lerche, Sanjay M. Sisodiya, Josemir W. Sander, Gianpiero L. Cavalleri, Bobby P.C. Koeleman, Mark McCormack, the EpiPGX Consortium

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)102-109
Number of pages8
JournalEpilepsia Open
Volume4
Issue number1
DOIs
Publication statusPublished - 1 Mar 2019
Externally publishedYes

Keywords

  • adverse effects
  • antiepileptic drugs
  • EpiPGX Consortium
  • GWAS
  • hyponatremia

Cite this

Berghuis, B., Stapleton, C., Sonsma, A. C. M., Hulst, J., de Haan, G. J., Lindhout, D., ... the EpiPGX Consortium (2019). A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine. Epilepsia Open, 4(1), 102-109. https://doi.org/10.1002/epi4.12297
Berghuis, Bianca ; Stapleton, Caragh ; Sonsma, Anja C.M. ; Hulst, Janic ; de Haan, Gerrit Jan ; Lindhout, Dick ; Demurtas, Rita ; Krause, Roland ; Depondt, Chantal ; Kunz, Wolfram S. ; Zara, Federico ; Striano, Pasquale ; Craig, John ; Auce, Pauls ; Marson, Anthony G. ; Stefansson, Hreinn ; O'Brien, Terence J. ; Johnson, Michael R. ; Sills, Graeme J. ; Wolking, Stefan ; Lerche, Holger ; Sisodiya, Sanjay M. ; Sander, Josemir W. ; Cavalleri, Gianpiero L. ; Koeleman, Bobby P.C. ; McCormack, Mark ; the EpiPGX Consortium. / A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine. In: Epilepsia Open. 2019 ; Vol. 4, No. 1. pp. 102-109.
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title = "A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine",
abstract = "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.",
keywords = "adverse effects, antiepileptic drugs, EpiPGX Consortium, GWAS, hyponatremia",
author = "Bianca Berghuis and Caragh Stapleton and Sonsma, {Anja C.M.} and Janic Hulst and {de Haan}, {Gerrit Jan} and Dick Lindhout and Rita Demurtas and Roland Krause and Chantal Depondt and Kunz, {Wolfram S.} and Federico Zara and Pasquale Striano and John Craig and Pauls Auce and Marson, {Anthony G.} and Hreinn Stefansson and O'Brien, {Terence J.} and Johnson, {Michael R.} and Sills, {Graeme J.} and Stefan Wolking and Holger Lerche and Sisodiya, {Sanjay M.} and Sander, {Josemir W.} and Cavalleri, {Gianpiero L.} and Koeleman, {Bobby P.C.} and Mark McCormack and {the EpiPGX Consortium}",
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Berghuis, B, Stapleton, C, Sonsma, ACM, Hulst, J, de Haan, GJ, Lindhout, D, Demurtas, R, 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 & the EpiPGX Consortium 2019, 'A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine', Epilepsia Open, vol. 4, no. 1, pp. 102-109. https://doi.org/10.1002/epi4.12297

A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine. / Berghuis, Bianca; Stapleton, Caragh; Sonsma, Anja C.M.; Hulst, Janic; de Haan, Gerrit Jan; Lindhout, Dick; Demurtas, Rita; Krause, Roland; Depondt, Chantal; Kunz, Wolfram S.; Zara, Federico; Striano, Pasquale; Craig, John; Auce, Pauls; Marson, Anthony G.; Stefansson, Hreinn; O'Brien, Terence J.; Johnson, Michael R.; Sills, Graeme J.; Wolking, Stefan; Lerche, Holger; Sisodiya, Sanjay M.; Sander, Josemir W.; Cavalleri, Gianpiero L.; Koeleman, Bobby P.C.; McCormack, Mark; the EpiPGX Consortium.

In: Epilepsia Open, Vol. 4, No. 1, 01.03.2019, p. 102-109.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

AU - Berghuis, Bianca

AU - Stapleton, Caragh

AU - Sonsma, Anja C.M.

AU - Hulst, Janic

AU - de Haan, Gerrit Jan

AU - Lindhout, Dick

AU - Demurtas, Rita

AU - Krause, Roland

AU - Depondt, Chantal

AU - Kunz, Wolfram S.

AU - Zara, Federico

AU - Striano, Pasquale

AU - Craig, John

AU - Auce, Pauls

AU - Marson, Anthony G.

AU - Stefansson, Hreinn

AU - O'Brien, Terence J.

AU - Johnson, Michael R.

AU - Sills, Graeme J.

AU - Wolking, Stefan

AU - Lerche, Holger

AU - Sisodiya, Sanjay M.

AU - Sander, Josemir W.

AU - Cavalleri, Gianpiero L.

AU - Koeleman, Bobby P.C.

AU - McCormack, Mark

AU - the EpiPGX Consortium

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - adverse effects

KW - antiepileptic drugs

KW - EpiPGX Consortium

KW - GWAS

KW - hyponatremia

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U2 - 10.1002/epi4.12297

DO - 10.1002/epi4.12297

M3 - Article

VL - 4

SP - 102

EP - 109

JO - Epilepsia Open

JF - Epilepsia Open

SN - 2470-9239

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ER -