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The genetic determinants of lamotrigine dosing in epilepsy

Grant, Matthew (2010) The genetic determinants of lamotrigine dosing in epilepsy. Masters thesis, University of Liverpool.

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Abstract

Introduction: Epilepsy is a common serious neurological disorder affecting approximately 50 million people worldwide. The mainstay of treatment is the use of antiepileptic drugs (AEDs), to which approximately 70% of people with epilepsy respond. Lamotrigine (LTG) was first licensed for use in the UK in 1991 and has become one of the most commonly prescribed AEDs in the developed world. It has proven efficacy for various epilepsy types, is employed at first-line treatment for partial-onset and generalised seizures, may be used for atonic, tonic, and atypical absence seizure types, and also has licensing for the treatment of Lennox-Gastaut syndrome. The individual dose of LTG required to achieve seizure freedom varies considerably,3 which may be at least partially explained by inter-individual variation in pharmacokinetic and pharmacodynamic profiles. Two proteins appear to be involved in the pharmacokinetics of LTG. UDP-glucuronosyl-transferase 1A4 (encoded by UGT1A4) is the enzyme responsible for the hepatic metabolism of LTG and organic cation transporter 1 (OCT1; encoded by SLC22A1) has very recently been implicated in the transport of LTG at the level of hepatocytes and the blood-brain-barrier. The pharmacodynamic profile of LTG is characterised by inhibition of neuronal voltage-gated sodium channels. The three predominant sodium channel alpha-subunits in mammalian brain are encoded by the genes SCN1A, SCN2A and SCN3A. We have assessed whether genetic variation in these five genes is associated with the maintenance dose of LTG when successfully employed as monotherapy in people with newly-diagnosed epilepsy. Methods: A total of 96 individuals with newly diagnosed epilepsy (50% male, mean age 42 years, range 9 to 83 years) who had been seizure-free for at least 12 months on an unchanged dose of LTG (median dose = 200 mg/day, range = 50 to 675 mg/day) were included in the analysis. A total of 173 single nucleotide polymorphisms (SNPs) across five genes (SCN1A, SCN2A, SCN3A, UGT1A4, SLC22A1) were genotyped and subjected to univariate and multivariate-regression analyses to identify associations with LTG maintenance dose. Multiple demographic factors (including age, gender, epilepsy type, previous AED use, and number of seizures prior to treatment) were also included as co-variates. Results: Univariate analyses revealed associations between maintenance dose and genotype at fourteen SNP loci, although these did not remain significant after correction for multiple comparisons using false-discovery rate. Multivariate regression analysis generated several models that associated with the observed variation in LTG maintenance dose. The most explanatory of these accomplished an r2-value of 0.606 (p<0.001) incorporating polymorphisms from SLC22A1, SCN1A, SCN2A and SCN3A. Conclusions: Genetic variation in SLC22A1, SCN3A and SCN2A, and to a lesser extent SCN1A, affect LTG maintenance dose requirement. These results require validation in a larger, independent cohort.

Item Type:Thesis (Masters)
Subjects:R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
R Medicine > RM Therapeutics. Pharmacology
Departments, Research Centres and Related Units:Academic Faculties, Institutes and Research Centres > Faculty of Medicine > School of Clinical Sciences
Refereed:No
Status:Unpublished
ID Code:1489
Deposited On:21 Sep 2011 16:45
Last Modified:06 Oct 2011 14:40

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