The Roles of Variants in Human Multidrug Resistance (MDR1) Gene and Their Haplotypes on Antiepileptic Drugs Response: A Meta-Analysis of 57 Studies

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.

Correlation between ABCB1 gene polymorphisms, antiepileptic drug concentrations and treatment response

“…Our data did not confirm the original report which noted an increased prevalence of the CC genotype in patients with resistant form of epilepsy. The present results are similar with a recently published meta-analysis of 57 case-controlled studies on C3435T, G2677T/A, and C1236T mutation influence over refractory epilepsy (31). In this meta-analysis, no difference between the frequency of observed alleles or genotypes in the population with refractory epilepsy was remarked, except for a significantly decreased risk of low therapeutic response to AEDs in patients who present T allele of C3435T variant in a Caucasian population.…”

Effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on oxcarbazepine concentrations and therapeutic efficacy in patients with epilepsy

“…One explanation may be the limited sample of Wang et al's study that enrolled 40 patients with epilepsy. A previous metaanalysis has concluded that ABCB1 rs1045642 polymorphism was not associated with drug resistance in patients with epilepsy [26], however recent studies showed the positive association, especially in Caucasians [27,28]. All the studies focused on various AEDs, to date, our study was the first analysis to evaluate the association between ABCB1 polymorphism and OXC therapeutic efficacy.…”

Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region

“…The MDR1 C3435T polymorphism is a silent mutation that decreases transporter expression and alters substrate specificity [ 130 , 131 ]; therefore, it has the potential to affect substrate absorption and tissue distribution. The resultant impact of this polymorphism on pharmacokinetic and pharmacodynamic outcomes of phenytoin therapy is unclear [ 7 , 130 , 132 ]. Three of the included studies investigated the MDR1 C3435T polymorphism [ 43 , 45 , 46 ].…”

“…Two studies conducted in Turkish patients with seizure disorders did not find a significant association between the MDR1 C3435T genotype and drug resistance [ 29 , 110 ]. More recently, a meta-analysis of studies conducted in Asian, Caucasian (under which populations originating from the MENA region were classified), and Indian populations investigated the role of MDR1 gene haplotypes in antiepileptic drug response [ 132 ]. Initial results indicated that the presence of the T variant of MDR1 C3435T may be associated with lower rates of drug resistance.…”

“…Initial results indicated that the presence of the T variant of MDR1 C3435T may be associated with lower rates of drug resistance. Once corrected for multiple statistical analyses, there was no significant association overall, but a significant association remained in Caucasian patients ( T vs. C allele, OR 0.83; 95% CI 0.71–0.96; p = 0.01) [ 132 ]. One hypothesis regarding inconsistency in positive associations found between MDR1 genotypes and responsiveness to antiepileptic drugs is that the gene falls within a significant block of high linkage disequilibrium [ 138 ].…”