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

Abstract

Objective: Previous 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.

Methods: The 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.

Results: A 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.

Conclusion: In 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.

Fig 1. Study selection procedures for a meta-analysis of MDR1 gene polymorphisms (C3435T, G2677T, and C1236T) with AEDs resistance.

AEDs: antiepileptic drugs; ABCB1: ATP-binding cassette sub-family B member 1.

Fig 2. Odds ratio (OR) estimates for the association between the ABCB1 C3435T polymorphism and AEDs resistance.

The sizes of the squares reflect theweighting of the included studies. Bars represent 95% CIs. The center of the diamond represents the summary effect; left and right points of the diamond represent the 95% CI. AEDs: antiepileptic drugs; CI: confidence interval; ABCB1: ATP-binding cassette sub-family B member 1.

Fig 3. Begg's funnel plots for publication bias test of the association between the ABCB1 C3435T polymorphism and AEDs resistance.

No significant funnel asymmetry that could indicate publication bias was observed. The horizontal line in the funnel plot indicates the random-effects summary estimate, and the sloping lines indicate the expected 95% confidence interval for a given standard error, assuming no heterogeneity between studies. Log(OR) is the natural logarithm of the odds ratio. AEDs: antiepileptic drugs; ABCB1: ATP-binding cassette sub-family B member 1.