Bioassay Unit, Herbal Medicine Research Center, Institute for Medical Research, Kuala Lumpur, Malaysia.
PLoS One. 2013 May 23;8(5):e64827. doi: 10.1371/journal.pone.0064827. Print 2013.
Carbamazepine (CBZ) is used as the first line of treatment of Complex Partial Seizures (CPS) in the Epilepsy Clinic, Neurology Department of Kuala Lumpur Hospital (KLH). More than 30% of the patients remain drug resistant to CBZ mono-therapy. CBZ is transported by the P-glycoprotein (P-gp). The P-gp encoded by the ABCB1 and ABCC2 genes are expressed in drug resistant patients with epilepsy. A few studies have shown significant association between CBZ resistant epilepsy and Linkage Disequilibrium (LD) with adjacent polymorphisms of these genes. Our study is aimed at determining the correlation between patients' response to CBZ mono-therapy to Single Nucleotide Polymorphisms G2677T and C3435T of the ABCB1 gene as well as G1249A and -24C>T of the ABCC2 gene.
314 patients with CPS were recruited from the Neurology Department of the KLH based on stringent inclusion and exclusion criteria, of whom 152 were responders and the other 162 were non-responders. DNA was extracted from their blood samples and Taqman technology for allelic discrimination was performed. Results were described as genotype frequencies. The SHEsis analysis platform was used to calculate linkage disequilibrium index and infer haplotype frequencies. Haploview was used to do permutation test to obtain a corrected p-value.
Resistance to treatment with CBZ mono-therapy was significantly associated with the 2677TT and the 3435TT genotypes while it was not significantly associated with the G1249A and -24C>T polymorphisms. The GCGC haplotype combination of the 2677G>T, 3435C>T, 1249G>A and -24C>T respectively was found to be extremely significant (p = 1.10e-20) with good drug response to CBZ mono-therapy.
Linkage disequilibrium between the 2677G>T, 3435C>T, 1249G>A and -24C>T SNPs may be used as a reliable screening marker to determine the treatment outcome of CBZ mono-therapy with CPS irrespective of race or gender.
卡马西平（CBZ）是吉隆坡医院（KLH）神经病学系癫痫诊所治疗复杂部分性发作（CPS）的一线药物。超过 30%的患者对 CBZ 单药治疗仍有耐药性。CBZ 由 P-糖蛋白（P-gp）转运。ABCB1 和 ABCC2 基因编码的 P-gp 在耐药性癫痫患者中表达。一些研究表明，CBZ 耐药性癫痫与这些基因的邻近多态性的连锁不平衡（LD）之间存在显著相关性。我们的研究旨在确定 CBZ 单药治疗患者对 ABCB1 基因的 G2677T 和 C3435T 以及 ABCC2 基因的 G1249A 和-24C>T 单核苷酸多态性的反应与单核苷酸多态性之间的相关性。
根据严格的纳入和排除标准，从 KLH 神经病学系招募了 314 名 CPS 患者，其中 152 名是反应者，另外 162 名是非反应者。从他们的血液样本中提取 DNA，并进行 Taqman 等位基因鉴别技术。结果以基因型频率描述。使用 SHEsis 分析平台计算连锁不平衡指数并推断单倍型频率。使用 Haploview 进行置换检验以获得校正的 p 值。
CBZ 单药治疗的耐药性与 2677TT 和 3435TT 基因型显著相关，而与 G1249A 和-24C>T 多态性无显著相关性。发现 2677G>T、3435C>T、1249G>A 和-24C>T 多态性的 GCGC 单倍型组合分别与 CBZ 单药治疗的良好药物反应显著相关（p=1.10e-20）。
2677G>T、3435C>T、1249G>A 和-24C>T 多态性之间的连锁不平衡可用作可靠的筛选标志物，用于确定 CPS 患者 CBZ 单药治疗的治疗结果，而与种族或性别无关。
