Genetic variants within glutathione S-transferase alpha 4 and their role in newly-diagnosed epilepsy


Mitchell, Paul Stephen (2012) Genetic variants within glutathione S-transferase alpha 4 and their role in newly-diagnosed epilepsy. [Staff Thesis]

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Abstract

Introduction: Epilepsy is one of the commonest neurological disorders, affecting over 50 million people worldwide. Antiepileptic drugs (AEDs) are the mainstay of treatment, though they remain ineffective in 30% of individuals for whom they are prescribed. Pharmacoresistance in epilepsy is a significant problem. The mechanisms involved elude us still, with numerous theories and hypotheses posed in order to explain why this phenotype may exist. It is thought that genetic variation within certain genes may explain, at least in part, why the pharmacoresistant phenotype exists, and indeed may explain the dose-response variation observed in clinical practise. A genome-wide association study was conducted on newly-diagnosed patients with epilepsy upon starting their first AED, with the primary measure of outcome being one year remission of seizures at any time during follow-up. The strongest association was seen at a loci on chromosome 6, rs622902 (p=1.47×10-7) in the glutathione S-transferase alpha 4 (GSTA4) gene. GSTA4 is an enzyme of the glutathione-conjugating family of superenzymes that are responsible for a plethora of reactions that detoxify reactive metabolic intermediates, including many xenobiotics. In view of these findings, it was the aim of this study to explore the role of GSTA4 in newly-diagnosed epilepsy patients. Methods: Seventeen tagging SNPs representing 48 alleles across the GSTA4 gene were genotyped in 541 SANAD and 390 Glasgow patients using TaqMan quantitative PCR and Sequenom matrix-assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF MS). Binary logistic regression and Cox proportional hazards multiple regression analyses were conducted in order to analyse patient remission (yes/no) of epilepsy, and time to 12-month remission of epilepsy, respectively. Six clinical covariates were adjusted for in the analysis: age, sex, epilepsy type (partial, generalised, unclassifiable), number of pre-treatment seizures (2, 3, 4, 5, >5), AED treatment (sodium valproate or gabapentin vs. neither) and EEG findings (normal, non-specific, epileptiform, not-done). Results: Three SNPs (rs6904769, FDR = 0.0353; rs6922246, FDR = 0.0109 and rs384505, FDR = 0.0459) in the SANAD cohort showed an association with the binary outcome (yes/no) of seizure remission. Only rs6922246 (FDR = 0.0459) held association after combining both cohorts. Two SNPs (rs6904769, FDR = 0.0491 and rs6922246, FDR = 0.00380) were significantly associated with time to 12-month remission of epilepsy. This association held in rs6922246 (FDR = 0.0459) after combining the cohorts. Conclusion: Polymorphism in rs6922246 may be associated with both the remission of epilepsy and the time to 12-month remission of epilepsy. Validation in an independent cohort is necessary to explore this link further.

Item Type: Staff Thesis
Additional Information: Date: 2012-08 (completed)
Subjects: ?? RC0321 ??
?? RM ??
Divisions: Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 28 Aug 2013 15:10
Last Modified: 16 Dec 2022 04:38
URI: https://livrepository.liverpool.ac.uk/id/eprint/10413
CORE (COnnecting REpositories)