Haerian B S, Roslan H, Raymond A A, Tan C T, Lim K S, Zulkifli S Z, Mohamed E H M, Tan H J, Mohamed Z
Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Seizure. 2010 Jul;19(6):339-46. doi: 10.1016/j.seizure.2010.05.004. Epub 2010 Jun 3.
The C3435T, a major allelic variant of the ABCB1 gene, is proposed to play a crucial role in drug-resistance in epilepsy. The C/C genotype carriers reportedly are at higher risk of pharmacoresistance to AEDs, but only in some studies. The hypothesis of the C-variant associated risk and resistance to antiepileptic drugs (AEDs) has been hampered by conflicting results from inadequate power in case-control studies. To assess the role of C3435T polymorphism in drug-resistance in epilepsy, a systematic review and meta-analysis was conducted.
Databases were obtained from the Cochrane Library, MEDLINE, EMBASE, major American and European conference abstracts, and www.google.my for genetic association studies up to February 2010. All the case-control association studies evaluating the role of ABCB1 C3435T in pharmacoresistance to AEDs were identified. The new definition of treatment outcome from International League Against Epilepsy (ILAE) was used for including studies for sub-analysis. To measure the strength of genetic association for the gene variant, the odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using models of both fixed- and random-effects for comparisons of the alleles and genotypes with co-dominant (C/C vs. T/T, C/T vs. T/T), dominant (C/C+C/T vs. T/T), and recessive (C/C vs. C/T+T/T) models in overall and in ethnicity subgroups. The 19 studies were selected for the next sub-analysis based on the new definition of drug-responsiveness and drug-resistance from ILAE. The same analysis was also performed for treatment outcome and ethnicity subgroups.
A total of 22 association studies including 3231 (47.8%) drug-resistant patients and 3524 (52.2%) drug-responsive patients or healthy controls (genotyped for C3435T) were pooled in this meta-analysis. The allelic association of ABCB1 C3435T with risk of drug-resistance was not significant under fixed-effects model, 1.06 (95% CI 0.98-1.14, p=0.12) and random-effects model, 1.10 (0.93-1.30, p=0.28) in overall and in the subgroup analysis by ethnicity. Similar results were also obtained for all genetic models in the stratified analyses by new definition of drug-resistance by ILAE and ethnicity subgroups. There was no publication bias.
We failed to show an association between the ABCB1 C3435T polymorphism and the risk of drug-resistance suggesting a revision in contribution of this polymorphism in the multi-drug transporters hypothesis of pharmacoresistance to AEDs in epilepsy.
ABCB1基因的主要等位基因变体C3435T被认为在癫痫耐药中起关键作用。据报道，C/C基因型携带者对抗癫痫药物（AEDs）产生耐药性的风险更高，但仅在部分研究中如此。病例对照研究样本量不足导致结果相互矛盾，阻碍了C变体与抗癫痫药物（AEDs）耐药性相关风险的假说验证。为评估C3435T多态性在癫痫耐药中的作用，进行了一项系统评价和荟萃分析。
通过检索Cochrane图书馆、MEDLINE、EMBASE、美国和欧洲主要会议摘要以及www.google.my获取截至2010年2月的基因关联研究数据库。纳入所有评估ABCB1 C3435T在AEDs耐药性中作用的病例对照关联研究。采用国际抗癫痫联盟（ILAE）对治疗结果的新定义纳入研究进行亚组分析。为衡量基因变体的遗传关联强度，使用固定效应模型和随机效应模型计算等位基因和基因型比较的优势比（ORs）及其95%置信区间（CIs），共显性模型（C/C vs. T/T，C/T vs. T/T）、显性模型（C/C+C/T vs. T/T）和隐性模型（C/C vs. C/T+T/T）用于总体及种族亚组分析。根据ILAE对药物反应性和耐药性的新定义，选择19项研究进行下一步亚组分析。对治疗结果和种族亚组也进行了同样的分析。
本荟萃分析共纳入2项关联研究，包括3231例（47.8%）耐药患者和3524例（52.2%）药物反应性患者或健康对照（进行了C3435T基因分型）。在固定效应模型下，ABCB1 C3435T与耐药风险的等位基因关联不显著，总体为1.06（95%CI 0.98 - 1.14，p = 0.12），种族亚组分析中随机效应模型为1.10（0.93 - 1.30，p = 0.28）。在按ILAE耐药新定义和种族亚组进行的分层分析中，所有遗传模型均得到类似结果。不存在发表偏倚。
我们未能证明ABCB1 C3435T多态性与耐药风险之间存在关联，这表明在癫痫AEDs耐药性的多药转运体假说中，该多态性的作用需重新审视。
