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 page: 25
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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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