| Epilepsy is one of the most common chronic neurological diseases in humans. Epileptic seizures result from abnormal, excessive synchronized discharge or hypersynchronous neuronal activity in the brain, with recurrent and unprovoked seizures. Meanwhile, seizure maybe causes transient disorder of the brain functions. It is characterized by the occurrence of one or more episodes of seizures and of the consequences of the corresponding neurobiology. The epileptic pathogenesis is unclear. In general, an imbalance between excitatory and inhibitory neurotransmission has been regarded to be the main cause of seizures.At present, more than50million people worldwide suffer from various types of epilepsy. In China, almost nine million people affected. The incidence of epilepsy is defined as the number of new cases within a year divided by the100,000of the population initially at risk. Or so1.5million people worldwide yearly suffer from new-onset of epileptic seizures, while300,000people in China yearly are affected by new-onset of epileptic seizures.Recently, some studies have shown that epilepsy is associated with genetic factors. The effectiveness of medication may vary from one patient to another, even for patients with the same syndrome. It is likely that these differences in responses to medication result, at least in part, from genetic factors. Enough evidences proved that the primary epilepsy is associated with genetics by genealogy, twins, electroencephalography studies and epidemilolgical investigation. Only approximately2%of cases of idiopathic epilepsy have been associated with monogenetic inheritance; most have been correlated with multiple genes. But various types of epilepsy do not all have clinical seizure.At present, treatment with antiepileptic drugs (AEDs) is the main approach to the control of epileptic seizures. Such therapy is used in an attempt to restore the balance between excitatory and inhibitory transmission. Clinically, medication for epilepsy is often required over a long period of time, even for a patient’s entire lifetime.Thus, the continuity of therapy of anti-epileptic drugs, which we refer to as’retention’in the present study, is extremely important. The ’retention rate’in the present study is defined as the percentage of patients who comply with treatment over a given period of time. Poor control of seizures and seizure relapse are common reasons for poor retention rates during the long-term epilepsy treatment.In other cases, allergic reactions and side-effects that affect the central nervous system (CNS), such as drowsiness, ataxia and fatigue, necessitate discontinuation of the drug. In this study, we focused on the efficacy, which is the decrease of seizure frequency after AEDs treatment. Efficacy was defined as the proportional decrease in the number of seizures between the first and last3months treatment period. Four semi-quantitative levels were used to assess the efficacy:seizure-free (SF), SF-75%,75-50%and <50%decrease in the number of seizures according to protocols of previous studies.In China, carbamazepine (CBZ) targets the sodium channel a-subunit type1(SCN1A), and is the most important first-line AED for medication of patients with simple partial seizures, complex partial seizures and secondary generalized seizures. Additionally, some adverse reactions might derivate from CBZ treatment, such as, allergic reaction, CNS side-effects, as well as disorders of cytopaenias, serum lipids and some transaminases. All these might be associated with CBZ dosage and plasma (serum) levels.So far, some investigations have revealed the association between SCN1A polymorphism and CBZ maintenance dose and serum level. Unfortunately, these studies did not investigate the association of SCN1A gene polymorphism with the retention rate of CBZ treatment. Actually, researchers who have investigated this issue have found it to be complicated and there are reports of conflicting results in different cohorts. In China, CBZ is used as the first-line AED to reduce the permeability of the SCN1A channel to Na+and Ca2+. In addition, studies have reported that CBZ may also potentiate gamma-aminobutyric acid (GABA) receptors, which comprise a1、β2and y2subunits (encoded by the GABRA1, GABRB2and GABRG2, respectively).The voltage-gated sodium channel asubunit type1(SCN1A) is heterologous complex, which comprises a large hollow glycosylation asubunit, encoded by SCN1A gene, and two small affiliated βsubunits encoded by SCN2A gene.They mainly distributed in the nerve and muscle. It is essential for the generation and propagation of action potentials. Functional researches indicated that sodium ion channel transmembranes a subunits are exceptionally expressed in the brain. Studies reported that the mutations of SCN1A gene are associated with various types of epileptic seizures.In the brains of mammals, the GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is y-aminobutyric acid (GABA), a major neurotransmitter in the central nervous system. Although GABA ends up producing an inhibitory effect on neurotransmitter release, GABA is not an inhibitory neurotransmitter itself as it stimulates the GABAA receptor; therefore, directly it is a stimulatory neurotransmitter. Upon activation, the GABAA receptor selectively conducts Cl-through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring. After activated, GABAa receptors selectively cause Cl" to transit and make neuronal hyperplarization. An inhibitory effect of the neurotranmitter is caused by reducing the opportunity of action potential generation.The aim of the this present study was to investigate whether the sodium channel asubunit type1(SCN1A), and GABAA receptor subunits genetic polymorphisms confer susceptibility to the patients with focal and complex focal seizures, secondary generalized seizures and focal seizures in Chinese population. Meanwhile, we also tried to elucidate the association between the polymorphisms of the target genes above mentioned and the retention rates, the maintenance dosage and serum levels, seizure decrease. The single nucleotide polymorphisms (SNPs) of the target genes included tag SNPs selected using HAPLOVIEW version4.2software (http://www.broad.mit.edu/haploview/haploview, accessed18Sept2009). Other SNPs in the promoter, exons and3’-untranslated (UTR) region that had potential function were also chosen.The major findings of the current studies are as follows:1. The SCN1A and GABAA receptor subunits genetic polymorphisms were not associated with epileptic susceptibility.2. The SCN1A rs3812718G/A polymorphism and GABRA1rs2290732G/A polymorphsim were associated with CBZ retention rate for epilepsy treatment. 3. The SCN1A rs3812718G/A polymorphism was associated with CBZ maintenance dose and serum level.4. The SCN1A rs2298771G/A polymorphism was associated with the efficacy of CBZ treatment for Chinese patients with focal and complex focal seizures, secondary generalized seizures and focal seizures. |
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