RLIP76 GENE VARIANTS ARE NOT ASSOCIATED WITH DRUG RESPONSE IN TURKISH EPILEPSY PATIENTS
Manguoğlu E1,*, Akdeniz S1, Dündar NO2, Duman Ö2, Aktekin B3, Haspolat Ş2, Bilge U4, Özel D4, Lüleci G1
*Corresponding Author: Esra Manguoğlu, Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya, Turkey; Tel.: +90-242-249-6977; Fax: +90-242-249-6906; E-mail: emanguoglu@akdeniz.edu.tr
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DISCUSSION

Approximately one-third of epilepsy patients remain untreated even though currently available drugs are used. Understanding the mechanism underlying drug response is crucial for better management strategies for drug resistant patients and may even lead to new drug discoveries. RLIP76 is one of these proteins that are proposed to have a role in AED transport mechanisms [4]. Our study is the first to investigate polymorphisms of the RLIP76 gene in Turkish patients. The Turkish population has a heterogeneous genetic background and high frequency of consanguinity which is around 33.9% in the Antalya region [14]. The polymorphisms we examined were mostly different from those cited by Soranzo et al. [11] and Leschziner et al. [12]. We found no correlation between the RLIP76 gene polymorphisms and drug response which agreed with both these studies. However, Awasthi et al. [4], showed that RLIP76 was expressed preferentially in the luminal surface of endothelial cell membranes of brain tissue and RLIP76 knockout mice had deficient phenytoin extrusion mechanisms in the blood-brain barrier. It was concluded that AED transport is done mainly by RLIP76 in the blood brain-barrier, therefore, it might be involved in drug resistance in epilepsy. Moreover, there is controversy regarding the location of RLIP76 in the cell and thus its function [15,16]. Our finding no linkage between drug response and the RLIP76 gene polymorphisms does not necessarily exclude RLIP76 having a possible role in drug response, given that the effects of nucleotide substitutions are not known. Several other factors may be involved in the drug resistance phenomena in epileptic patients [2,3]. However, the reported results are conflicting. A striking example is the synonymous SNP, C3435T [17]. However, a recent meta-analysis, in which genotype association results for 3,231 drug-resistant patients and 3,524 drug-responsive or healthy controls were analyzed, failed to show any association between the ABCB1 gene C3435T genotype and drug response in epilepsy [18]. Thus, this polymorphism seems unlikely to have an effect in predisposition to drug resistance. Zang et al. [19] have shown that human P-glycoprotein can transport phenytoin and phenobarbital in a concentration dependent fashion. However, the antiepileptic drugs carbamazepine, vaproic acid, phenytoin, lamotrigine and primidone were shown not to interact with ABCB1, ABCC1 and ABCC2 transporters in drug-resistant cancer cell lines [20]. Likewise, carbamazepine, valproate, levetiracetam, phenytoin, lamotrigine and phenobarbital have been shown not to be substrates of human MRP1, 2 and 5 in kidney cell lines [21]. These controversial data may result from factors such as the drugs used, patient demographic characteristics and epilepsy subtypes. Moreover, other genetic variants have been shown to be associated with drug response in epileptic patients. A recent study of the association between polymorphisms of the CYP2C9, CYP2C19, UGT1A1, UGT2B7, ABCB1, SCN1A genes and drug resistance found no significant association, but stratification by patient age and etiology yielded significant correlation between certain ABCB1 genotypes, patients with symptomatic epilepsy and risk of drug resistance [22]. Although there are many promising results available in the current literature, the exact factors involved in drug resistance in epilepsy have yet to be identified. Important obstacles to progress in this field may be the patient selection criteria and the definition of drug responsiveness and of refractory patients [23]. These might differ between publications and might create bias. Indeed, 20.42% of 191 drug refractory epilepsy patients were found to be pseudo refractory. That is, factors causing seizures are extraneous and reevaluation of treatment would result in reduction in the number of refractory epilepsy cases [24]. In addition, optimal doses of AEDs show great variation between individuals. Therefore, it might be useful to evaluate genetic variations from two perspectives: 1) that might affect clinical efficacy of AEDs such as drug absorption, distribution and targets, and 2) that might affect tolerability and safety that are adverse reactions of AEDs, as suggested by Löscher et al. [17]. For instance, an allele of the MRP2 gene c.1247G>A polymorphism was found to be strongly associated with the adverse drug reactions of carbamazepine in 146 patients with epilepsy and in 279 patients in a replication study [25]. Indeed, in a study, which included 809 patients, to evaluate adverse effects of AEDs and their relationship with a number of co-prescribed AEDs and AED loads, it was suggested that adverse effects are more prominent with individual susceptibility, AED type, and skills of the physicians than the number of co-prescribed AEDs and their load [26]. Multiple mechanisms probably underlie the phenotype. Therefore, combined effects of multiple genes and other factors, should be investigated with large families and larger sample sizes, and therefore, multi-centric collaborations are needed, especially for polymorphisms with minor allele frequencies.



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