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

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Bianca Berghuis Caragh Stapleton Anja C. M. Sonsma Janic Hulst Gerrit‐Jan de Haan Dick Lindhout Rita Demurtas The 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 L. Cavalleri Bobby P. C. Koeleman Mark McCormack

https://doi.org/10.1002/epi4.12297

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.

Skills

Posted on

03/10/2020