The roles of variants in human multidrug resistance (MDR1) gene and their haplotypes on antiepileptic drugs response: a meta-analysis of 57 studies.

Hui Li,Cheng Chang,Bing Wang,Yun Xu,Yajun Jiang,Minghua Wu,Qing Song

doi:10.1371/journal.pone.0122043

Abstract

ObjectivePrevious studies reported the associations between the ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1) polymorphisms and their haplotypes with risk of response to antiepileptic drugs in epilepsy, however, the results were inconclusive.MethodsThe Pubmed, Embase, Web of Science, CNKI and Chinese Biomedicine databases were searched up to July 15, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model based on heterogeneity tests. Meta-regression and Galbraith plot analysis were carried out to explore the possible heterogeneity.ResultsA total of 57 studies involving 12407 patients (6083 drug-resistant and 6324 drug-responsive patients with epilepsy) were included in the pooled-analysis. For all three polymorphisms (C3435T, G2677T/A, and C1236T), we observed a wide spectrum of minor allele frequencies across different ethnicities. A significantly decreased risk of AEDs resistance was observed in Caucasian patients with T allele of C3435T variant, which was still significant after adjusted by multiple testing corrections (T vs C: OR=0.83, 95%CI=0.71-0.96, p=0.01). However, no significant association was observed between the other two variants and AEDs resistance. Of their haplotypes in ABCB1 gene (all studies were in Indians and Asians), no significant association was observed with AEDs resistance. Moreover, sensitivity and Cumulative analysis showed that the results of this meta-analysis were stable.ConclusionIn summary, this meta-analysis demonstrated that effect of C3435T variant on risk of AEDs resistance was ethnicity-dependent, which was significant in Caucasians. Additionally, further studies in different ethnic groups are warranted to clarify possible roles of haplotypes in ABCB1 gene in AEDs resistance, especially in Caucasians.

Highlights

For all three polymorphisms (C3435T, G2677T/A, and C1236T), we observed a wide spectrum of minor allele frequencies across different ethnicities
A significantly decreased risk of antiepileptic drugs (AEDs) resistance was observed in Caucasian patients with T allele of C3435T variant, which was still significant after adjusted by multiple testing corrections (T vs C: odds ratios (ORs)=0.83, 95%confidence intervals (CIs)=0.71-0.96, p=0.01)
No significant association was observed between the other two variants and AEDs resistance. Of their haplotypes in ABCB1 gene, no significant association was observed with AEDs resistance

Summary

Introduction

The ATP-binding cassette sub-family B member 1 (ABCB1, known as MDR1) gene, which encodes human P-glycoprotein, can transport several AEDs.[9] In addition, previous studies have demonstrated that ABCB1 was overexpressed in brain tissue from patients with refractory epilepsy, suggesting ABCB1 gene might be an important candidate gene responsible for refractory epilepsy.[10, 11] Siddiqui et al first reported that patients with drugresistant epilepsy were more likely to have the CC genotype in C3435T variant, a wellknown polymorphism in ABCB1 gene [12]. An accumulating number of studies focused on the association between three polymorphisms (C3435T, G2677T/A, and C1236T) in ABCB1 gene and responsiveness to AEDs, the results were contradictory, mainly due to studies with ethnic differences, limited sample sizes, and inadequate statistical power

Methods

Results

Conclusion