Influence of the SCN1A IVS5N + 5 G>A Polymorphism on Therapy with Carbamazepine for Epilepsy

Balkan Journal of Medical Genetics - Tập 15 Số 1 - Trang 19-24 - 2012
Zoran Sterjev1, Gordana Kiteva2, Emilija Cvetkovska2, I. Petrov2, Igor Kuzmanovski2, Teodora Ribarska3, KA Nestorovska1, Nadica Matevska1, S Trajkovik-Jolevska3, Aleksandar Dimovski1, Ljubica Šuturkova1
1Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, University "St. Cyril and Methodius, Skopje, Republic of Macedonia1
2Clinic of Neurology, Faculty of Medicine, University "St. Cyril and Methodius, Skopje, Republic of Macedonia2
3Institute for Pharmaceutical Analysis, Faculty of Pharmacy, University "St. Cyril and Methodius, Skopje, Republic of Macedonia3

Tóm tắt

Influence of the SCN1A IVS5N + 5 G>A Polymorphism on Therapy with Carbamazepine for EpilepsyCarbamazepine (CBZ) blocks neuronal sodium channels in a voltage- and frequency-dependent manner, delaying the recovery of the channels from the inactivated state, reducing the number of action potentials within a burst, and decreasing burst duration. The α-subunit of the first neuronal sodium channel (SCN1A) is a major gene in different epilepsies. A synonymous polymorphism (SCN1A IVS5N + 5 G>A or rs3812718) is common in exon 5 of this gene. Mutations in the α-unit of this gene are associated with CBZ-resistant epilepsy and a higher maintenance dose of CBZ. We have investigated the association of this single nucleotide polymorphism (SNP) and epilepsy, efficacy and dose-dependence of CBZ therapy in 147 adult Macedonian patients and 137 non epileptic controls. No significant differences in allelic frequencies and genotype distribution were found between patients and controls (p = 0.94278), or between CBZ-responsive and unresponsive patients (p = 0.55449). An association between the A allele and a higher maintenance dose in CBZ-responsive patients was detected. No statistical difference was found between the plasma levels of CBZ and genotype of patients receiving the same dose, indicating that the variant exerts its effect at the level of receptor responsiveness. The predictive value of pretreatment testing showed a minor insignificant difference between patients with different genotypes, primarily due to a small number of patients.

Từ khóa


Tài liệu tham khảo

W. Löscher, 2009, The clinical impact of pharmacogenetics on the treatment of epilepsy, Epilepsia, 50, 1, 10.1111/j.1528-1167.2008.01716.x

F. Yu, 2003, Overview of the voltage-gated sodium channel family, Genome Biol, 4, 207, 10.1186/gb-2003-4-3-207

A George, Jr, 2005, Inherited disorders of voltage-gated sodium channels, J Clin Invest, 115, 1990, 10.1172/JCI25505

N. Plummer, 1999, Evolution and diversity of mammalian sodium channel genes, Genomics, 57, 323, 10.1006/geno.1998.5735

S. Tate, 2005, Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin, Proc Natl Acad Sci USA, 102, 5507, 10.1073/pnas.0407346102

S. Tate, 2006, A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose, Pharmacogenet Genomics, 16, 721, 10.1097/01.fpc.0000230114.41828.73

T. Abe, 2008, Association between SCN1A polymorphism and carbamazepine-resistant epilepsy, Br J Clin Pharmacol, 66, 304, 10.1111/j.1365-2125.2008.03203.x

F. Zimprich, 2008, A functional polymorphism in the SCN1A gene is not associated with carbamazepine dosages in Austrian patients with epilepsy, Epilepsia, 49, 1108, 10.1111/j.1528-1167.2008.01549_4.x

E. Heinzen, 2007, Nova2 interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A, Am J Hum Genet, 80, 876, 10.1086/516650

C. Thompson, 2011, SCN1A splice variants exhibit divergent sensitivity to commonly used antiepileptic drugs, Epilepsia, 52, 1000, 10.1111/j.1528-1167.2011.03040.x

M. Sánchez, 2010, Genetic factors associated with drug-resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy, Seisure, 19, 93

I. Manna, 2011, A functional polymorphism in the SCN1A gene does not infl uence antiepileptic drug responsiveness in Italian patients with focal epilepsy, Epilepsia, 52, 1528, 10.1111/j.1528-1167.2011.03097.x

C. Depondt, 2006, The potential of pharmacogenetics in the treatment of epilepsy, Eur J Paediatr Neurol, 10, 57, 10.1016/j.ejpn.2005.11.009

Thông tin
Thông tin xuất bản

Balkan Journal of Medical Genetics

Tập 15 Số 1

19-24

Thông tin tác giả