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. 2019 Jan 17;4(1):102-109.
doi: 10.1002/epi4.12297. eCollection 2019 Mar.

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

Bianca Berghuis  1 , Caragh Stapleton  2 , Anja C M Sonsma  3 , Janic Hulst  1 , Gerrit-Jan de Haan  1 , Dick Lindhout  1   3 , Rita Demurtas  4 ; EpiPGX Consortium; Roland Krause  5 , Chantal Depondt  6 , Wolfram S Kunz  7 , Federico Zara  8 , Pasquale Striano  9 , John Craig  10 , Pauls Auce  11 , Anthony G Marson  11 , Hreinn Stefansson  12 , Terence J O'Brien  13 , Michael R Johnson  14 , Graeme J Sills  11 , Stefan Wolking  15 , Holger Lerche  15 , Sanjay M Sisodiya  4   16 , Josemir W Sander  1   4   16 , Gianpiero L Cavalleri  2   17 , Bobby P C Koeleman  3 , Mark McCormack  2   3
Collaborators, Affiliations

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

Bianca Berghuis et al. Epilepsia Open. .

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: EpiPGX Consortium; GWAS; adverse effects; antiepileptic drugs; hyponatremia.

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Figures

Figure 1
Figure 1
Manhattan and Q‐Q plots of sodium levels (λ = 1.00)
Figure 2
Figure 2
Manhattan and Q‐Q plots of COIH (λ = 1.00)
Figure 3
Figure 3
Manhattan and Q‐Q plots of carbamazepine metabolic ratio (λ = 0.98)
See this image and copyright information in PMC

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