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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Relationship between <italic>ABCB1</italic> 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis</title><author><name sortKey="Chouchi, Malek" sort="Chouchi, Malek" uniqKey="Chouchi M" first="Malek" last="Chouchi">Malek Chouchi</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Department of Genetic,</institution><institution>Tunis El Manar University, Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">Department of Child Neurology, National Institute Mongi Ben Hmida of Neurology, UR12SP24 Abnormal Movements of Neurologic Diseases, Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Kaabachi, Wajih" sort="Kaabachi, Wajih" uniqKey="Kaabachi W" first="Wajih" last="Kaabachi">Wajih Kaabachi</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Division of Histology and Immunology Division, Department of Basic Sciences,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Klaa, Hedia" sort="Klaa, Hedia" uniqKey="Klaa H" first="Hedia" last="Klaa">Hedia Klaa</name><affiliation><nlm:aff id="Aff2">Department of Child Neurology, National Institute Mongi Ben Hmida of Neurology, UR12SP24 Abnormal Movements of Neurologic Diseases, Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Tizaoui, Kalthoum" sort="Tizaoui, Kalthoum" uniqKey="Tizaoui K" first="Kalthoum" last="Tizaoui">Kalthoum Tizaoui</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Division of Histology and Immunology Division, Department of Basic Sciences,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Turki, Ilhem Ben Youssef" sort="Turki, Ilhem Ben Youssef" uniqKey="Turki I" first="Ilhem Ben-Youssef" last="Turki">Ilhem Ben-Youssef Turki</name><affiliation><nlm:aff id="Aff2">Department of Child Neurology, National Institute Mongi Ben Hmida of Neurology, UR12SP24 Abnormal Movements of Neurologic Diseases, Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Hila, Lamia" sort="Hila, Lamia" uniqKey="Hila L" first="Lamia" last="Hila">Lamia Hila</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Department of Genetic,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28202008</idno><idno type="pmc">5311838</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311838</idno><idno type="RBID">PMC:5311838</idno><idno type="doi">10.1186/s12883-017-0801-x</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000042</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000042</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Relationship between <italic>ABCB1</italic> 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis</title><author><name sortKey="Chouchi, Malek" sort="Chouchi, Malek" uniqKey="Chouchi M" first="Malek" last="Chouchi">Malek Chouchi</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Department of Genetic,</institution><institution>Tunis El Manar University, Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">Department of Child Neurology, National Institute Mongi Ben Hmida of Neurology, UR12SP24 Abnormal Movements of Neurologic Diseases, Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Kaabachi, Wajih" sort="Kaabachi, Wajih" uniqKey="Kaabachi W" first="Wajih" last="Kaabachi">Wajih Kaabachi</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Division of Histology and Immunology Division, Department of Basic Sciences,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Klaa, Hedia" sort="Klaa, Hedia" uniqKey="Klaa H" first="Hedia" last="Klaa">Hedia Klaa</name><affiliation><nlm:aff id="Aff2">Department of Child Neurology, National Institute Mongi Ben Hmida of Neurology, UR12SP24 Abnormal Movements of Neurologic Diseases, Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Tizaoui, Kalthoum" sort="Tizaoui, Kalthoum" uniqKey="Tizaoui K" first="Kalthoum" last="Tizaoui">Kalthoum Tizaoui</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Division of Histology and Immunology Division, Department of Basic Sciences,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Turki, Ilhem Ben Youssef" sort="Turki, Ilhem Ben Youssef" uniqKey="Turki I" first="Ilhem Ben-Youssef" last="Turki">Ilhem Ben-Youssef Turki</name><affiliation><nlm:aff id="Aff2">Department of Child Neurology, National Institute Mongi Ben Hmida of Neurology, UR12SP24 Abnormal Movements of Neurologic Diseases, Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author><author><name sortKey="Hila, Lamia" sort="Hila, Lamia" uniqKey="Hila L" first="Lamia" last="Hila">Lamia Hila</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Department of Genetic,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</nlm:aff></affiliation></author></analytic><series><title level="j">BMC Neurology</title><idno type="eISSN">1471-2377</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Antiepileptic drugs (AEDs) are effective medications available for epilepsy. However, many patients do not respond to this treatment and become resistant. Genetic polymorphisms may be involved in the variation of AEDs response. Therefore, we conducted an updated systematic review and a meta-analysis to investigate the contribution of the genetic profile on epilepsy drug resistance.</p></sec><sec><title>Methods</title><p>We proceeded to the selection of eligible studies related to the associations of polymorphisms with resistance to AEDs therapy in epilepsy, published from January 1980 until November 2016, using Pubmed and Cochrane Library databases. The association analysis was based on pooled odds ratios (ORs) and 95% confidence intervals (CIs).</p></sec><sec><title>Results</title><p>From 640 articles, we retained 13 articles to evaluate the relationship between ATP-binding cassette sub-family C member 1 (<italic>ABCB1</italic>) C3435T polymorphism and AEDs responsiveness in a total of 454 epileptic AEDs-resistant cases and 282 AEDs-responsive cases. We found a significant association with an OR of 1.877, 95% CI 1.213–2.905. Subanalysis by genotype model showed a more significant association between the recessive model of <italic>ABCB1</italic> C3435T polymorphism (TT vs. CC) and the risk of AEDs resistance with an OR of 2.375, 95% CI 1.775–3.178 than in the dominant one (CC vs. TT) with an OR of 1.686, 95% CI 0.877–3.242.</p></sec><sec><title>Conclusion</title><p>Our results indicate that <italic>ABCB1</italic> C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy. As genetic screening of this genotype may be useful to predict AEDs response before starting the treatment, further investigations should validate the association.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Depont, C" uniqKey="Depont C">C Depont</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moshe, Sl" uniqKey="Moshe S">SL Moshé</name></author><author><name sortKey="Perucca, E" uniqKey="Perucca E">E Perucca</name></author><author><name sortKey="Ryvlin, P" uniqKey="Ryvlin P">P Ryvlin</name></author><author><name sortKey="Tomson, T" uniqKey="Tomson T">T Tomson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kwan, P" uniqKey="Kwan P">P Kwan</name></author><author><name sortKey="Arzimanoglou, A" uniqKey="Arzimanoglou A">A Arzimanoglou</name></author><author><name sortKey="Berg, At" uniqKey="Berg A">AT Berg</name></author><author><name sortKey="Brodie, 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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Neurol</journal-id><journal-id journal-id-type="iso-abbrev">BMC Neurol</journal-id><journal-title-group><journal-title>BMC Neurology</journal-title></journal-title-group><issn pub-type="epub">1471-2377</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28202008</article-id><article-id pub-id-type="pmc">5311838</article-id><article-id pub-id-type="publisher-id">801</article-id><article-id pub-id-type="doi">10.1186/s12883-017-0801-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Relationship between <italic>ABCB1</italic> 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" equal-contrib="yes"><name><surname>Chouchi</surname><given-names>Malek</given-names></name><address><email>chch.m@hotmail.fr</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Kaabachi</surname><given-names>Wajih</given-names></name><address><email>kaabachi.wajih@gmail.com</email></address><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Klaa</surname><given-names>Hedia</given-names></name><address><email>hedia.klaa@gmail.com</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Tizaoui</surname><given-names>Kalthoum</given-names></name><address><email>kalttizaoui@gmail.com</email></address><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Turki</surname><given-names>Ilhem Ben-Youssef</given-names></name><address><email>ilhem.benyoussef58@gmail.com</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hila</surname><given-names>Lamia</given-names></name><address><email>lamia_hila@yahoo.fr</email></address><xref ref-type="aff" rid="Aff4">4</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Department of Genetic,</institution><institution>Tunis El Manar University, Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</aff><aff id="Aff2"><label>2</label>Department of Child Neurology, National Institute Mongi Ben Hmida of Neurology, UR12SP24 Abnormal Movements of Neurologic Diseases, Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Division of Histology and Immunology Division, Department of Basic Sciences,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000000122959819</institution-id><institution-id institution-id-type="GRID">grid.12574.35</institution-id><institution>Department of Genetic,</institution><institution>Faculty of Medicine of Tunis,</institution></institution-wrap>15 Jebel Lakhdhar street, La Rabta, 1007 Tunis, Tunisia</aff></contrib-group><pub-date pub-type="epub"><day>15</day><month>2</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>2</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>17</volume><elocation-id>32</elocation-id><history><date date-type="received"><day>28</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>19</day><month>1</month><year>2017</year></date></history><permissions><copyright-statement>© The Author(s). 2017</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p>Antiepileptic drugs (AEDs) are effective medications available for epilepsy. However, many patients do not respond to this treatment and become resistant. Genetic polymorphisms may be involved in the variation of AEDs response. Therefore, we conducted an updated systematic review and a meta-analysis to investigate the contribution of the genetic profile on epilepsy drug resistance.</p></sec><sec><title>Methods</title><p>We proceeded to the selection of eligible studies related to the associations of polymorphisms with resistance to AEDs therapy in epilepsy, published from January 1980 until November 2016, using Pubmed and Cochrane Library databases. The association analysis was based on pooled odds ratios (ORs) and 95% confidence intervals (CIs).</p></sec><sec><title>Results</title><p>From 640 articles, we retained 13 articles to evaluate the relationship between ATP-binding cassette sub-family C member 1 (<italic>ABCB1</italic>) C3435T polymorphism and AEDs responsiveness in a total of 454 epileptic AEDs-resistant cases and 282 AEDs-responsive cases. We found a significant association with an OR of 1.877, 95% CI 1.213–2.905. Subanalysis by genotype model showed a more significant association between the recessive model of <italic>ABCB1</italic> C3435T polymorphism (TT vs. CC) and the risk of AEDs resistance with an OR of 2.375, 95% CI 1.775–3.178 than in the dominant one (CC vs. TT) with an OR of 1.686, 95% CI 0.877–3.242.</p></sec><sec><title>Conclusion</title><p>Our results indicate that <italic>ABCB1</italic> C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy. As genetic screening of this genotype may be useful to predict AEDs response before starting the treatment, further investigations should validate the association.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Epilepsy</kwd><kwd>Antiepileptic drugs</kwd><kwd>Resistance</kwd><kwd><italic>ABCB1</italic> C3435T polymorphism</kwd><kwd>Meta-analysis</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2017</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p>Epilepsy is a chronic neurological worldwide disorder [<xref ref-type="bibr" rid="CR1">1</xref>]. Most cases of epileptic patients respond to antiepileptic drugs (AEDs). However, about one-third of epileptic patients develop recurrent seizures, despite the efficacy of treatment at the optimal dose regimen. They are then, considered resistant to antiepileptic treatment [<xref ref-type="bibr" rid="CR2">2</xref>]. The international league against epilepsy (ILAE) redefined refractory epilepsy in 2010 as the persistence of seizures after two adequate trials of appropriate and tolerated AEDs [<xref ref-type="bibr" rid="CR3">3</xref>].</p><p>The exact mechanism of refractory epilepsy is not well understood. Two main hypotheses are potentially involved in the biological mechanism of AEDs resistance: transporter and target hypotheses. The transporter hypothesis supports the overexpression of drug efflux transporters at the blood–brain barrier (BBB) reducing AEDs access to the brain. The target hypothesis contends that the changes in drug intracellular target sites (receptors) result in decreased sensitivity of AEDs [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR5">5</xref>]. Therefore, the two mechanisms prevent pharmacological effects of antiepileptic at cerebral sites initiating seizures. It seems that genetic polymorphisms of drug transporter and target genes have a potential impact on the resistance to treatment: they may be responsible for the mechanisms of intractable epilepsy [<xref ref-type="bibr" rid="CR5">5</xref>–<xref ref-type="bibr" rid="CR7">7</xref>] by changing the function of genes products [<xref ref-type="bibr" rid="CR8">8</xref>–<xref ref-type="bibr" rid="CR10">10</xref>] and leading to the AEDs failure [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR11">11</xref>–<xref ref-type="bibr" rid="CR14">14</xref>]. Moreover, other authors have suggested that they may involve the prognosis of newly treated epilepsy [<xref ref-type="bibr" rid="CR15">15</xref>]. Since drug-resistant epilepsy represents a major problem in the control of seizures, the researchers focused on the genetic profile to try to better understand the pharmacoresistance for a more effective treatment.</p><p>Since drug resistance often occurs in patients with multiple AEDs, the multidrug transporter hypothesis is considered better than the target hypothesis to explain the phenomenon of AEDs resistant epilepsy. However, the two hypotheses may complement each other. Given that drug transport mechanisms are the candidate mechanisms underlying AEDs resistance [<xref ref-type="bibr" rid="CR16">16</xref>], many studies took significantly into consideration the association between efflux transporters overexpression inducing recurrent seizures.</p><p>Bioavailability and response to medication in epilepsy are mainly influenced by atp-binding cassette (ABC) transporter superfamily. The atp-binding cassette sub-family b member 1 (<italic>ABCB1</italic>) and the atp-binding cassette sub-family c member 2 (<italic>ABCC2</italic>) also known as multidrug resistance protein 1 (<italic>MDR1</italic>) and multidrug resistance protein 2 (<italic>MDR2</italic>), located at the membrane of BBB endothelial cells, are members of the ABC superfamily. They are the most studied candidate genes in pharmacoresistant epilepsy [<xref ref-type="bibr" rid="CR5">5</xref>]. P-glycoprotein (P-gp) was the first human ABC protein that has been discovered [<xref ref-type="bibr" rid="CR17">17</xref>]. <italic>ABCB1</italic> gene encodes it and it affects a wide range of drugs distribution in target compartments [<xref ref-type="bibr" rid="CR18">18</xref>–<xref ref-type="bibr" rid="CR20">20</xref>]. The C3435T polymorphism is the most investigated polymorphism in the <italic>ABCB1</italic> gene (single nucleotide polymorphism (SNP) in exon 26) and it has received the most attention. It has been associated with the variations in the expression levels of P-gp [<xref ref-type="bibr" rid="CR21">21</xref>]. Previous studies focusing on the association between <italic>ABCB1</italic> C3435T polymorphism and drug-resistant epilepsy showed discordant findings. Several studies have supported the hypothesis of this association (alleles, genotypes or haplotypes) to AEDs resistance [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR37">37</xref>]. However, a number of studies conducted on epileptic patients from different regions and ethnicities failed to confirm this result [<xref ref-type="bibr" rid="CR38">38</xref>–<xref ref-type="bibr" rid="CR42">42</xref>]. Subsequently, the opposed findings stimulated some previous meta-analyses of which the majority indicated that no association existed [<xref ref-type="bibr" rid="CR43">43</xref>–<xref ref-type="bibr" rid="CR49">49</xref>]. Besides, G1249A polymorphism is one of the common polymorphisms in the <italic>ABCC2</italic> gene (SNP in exon 10). The overexpression of the ABCC2 transporter protein reduces AEDs levels in brain tissues, which is a risk factor for pharmacoresistant epilepsy. A genotypic association between this polymorphism and responsiveness to AEDs has been suggested in Asian populations [<xref ref-type="bibr" rid="CR50">50</xref>, <xref ref-type="bibr" rid="CR51">51</xref>]. However, other studies published contradictory results and they did not find any association [<xref ref-type="bibr" rid="CR42">42</xref>, <xref ref-type="bibr" rid="CR52">52</xref>–<xref ref-type="bibr" rid="CR56">56</xref>]. Furthermore, only two meta-analyses investigated its role in drug-resistant epilepsy and found that <italic>ABCC2</italic> G1249A polymorphism was significantly associated with the decreased risk of AED resistance [<xref ref-type="bibr" rid="CR57">57</xref>, <xref ref-type="bibr" rid="CR58">58</xref>].</p><p>Among their pharmacological effects, some AEDs may block voltage-dependent sodium channels [<xref ref-type="bibr" rid="CR59">59</xref>, <xref ref-type="bibr" rid="CR60">60</xref>], which stimulate the researchers to investigate the potential link between drug-resistant epilepsy and polymorphisms in channels genes like <italic>SCN1A</italic> gene. This gene is the most studied drug target gene in epilepsy and it exhibits an intronic polymorphism IVS5-91G > A, one of the most common polymorphisms (SNP at intron splice donor site of exon 5). It alters the proportion of human brain NaV1.1-5N (exon 5N) and NaV1.1-5A (exon 5A) proteins, but the functional impact of the splicing on NaV1.1 is unknown. The correlation between <italic>SCN1A</italic> IVS5-91G > A polymorphism and maximum doses of Oxcarbazepine (OXC) may have a potential effect on resistant to epilepsy. The same study found the same correlation for <italic>ABCC2</italic> G1249A polymorphism [<xref ref-type="bibr" rid="CR61">61</xref>]. An additional study reported a genotypic association of <italic>SCN1A</italic> IVS5-91G > A polymorphism with the response to Carbamazepine (CBZ)/OXC [<xref ref-type="bibr" rid="CR51">51</xref>, <xref ref-type="bibr" rid="CR62">62</xref>], and another one showed its role on pharmacoresponse to CBZ via an effect on GABAergic cortical interneurons [<xref ref-type="bibr" rid="CR63">63</xref>]. However, other studies [<xref ref-type="bibr" rid="CR64">64</xref>–<xref ref-type="bibr" rid="CR66">66</xref>] and only one meta-analysis [<xref ref-type="bibr" rid="CR67">67</xref>] were unable to replicate this association.</p><p>Overall, even the most considered polymorphisms that may explain mechanisms of pharmacoresistant epilepsy, showed contradictory and inclusive results. Therefore, we assembled pharmacogenetics (PGt) and pharmacogenomics (PGx) studies reporting associations between AEDs resistant epilepsy and eventual polymorphisms. Then, we performed an updated meta-analysis to clarify their role in response to AEDs.</p></sec><sec id="Sec2"><title>Methods</title><p>We defined search strategy, study selection criteria, data elements and methods for study quality assessment.</p><sec id="Sec3"><title>Data sources and literature searches</title><p>We conducted a literature search using Pubmed and Cochrane Library with English-language restriction from January 1980 to November 2016. The key words used in the search strategy were: “anti-epileptic drug(s)”, “antiepileptic drug(s)”, “anti epileptic drug(s)” and “epilepsy” and “efficacy”, “intractable”, “refractory”, “resistance”, “resistant”, “response to treatment”, “pharmacoresistance”, “pharmacoresistant” and “genetic factor(s)”, “genotype(s)”, “pharmacogenetic(s)”, “pharmacogenomic(s)”, “polymorphism(s)”, “variant(s)”, “variation(s)”, “SNP(s)”. We did not search of additional publications. The reported results followed the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA).</p></sec><sec id="Sec4"><title>Eligibility and inclusion criteria</title><p>For eligibility, we retained full-text publications showing a relationship between genetic polymorphisms and responsiveness of AEDs in epilepsy (monotherapy or polytherapy).</p><p>The included studies met the following criteria: 1) Original research articles reported a genotypic evaluation of polymorphisms and resistant epilepsy to antiepileptic treatment. 2) Studies compared AEDs-resistant cases with AEDs-responsive cases. 3) Studies showed sufficient individual genotype frequencies for specific genotype model. 4) At least three studies on the same polymorphism were available in order to avoid the non-pertinence of the results and the high risk of bias.</p></sec><sec id="Sec5"><title>Data extraction</title><p>Two independent authors performed the data eligibility, they extracted the following information from each included study: first author, publication year, ethnicity of the study population, the number of cases and controls, genotype model for each polymorphism, age, gender, aetiology, type of epilepsy, and AEDs administered.</p></sec><sec id="Sec6"><title>Data synthesis and analysis</title><p>We calculated the association between polymorphisms and AEDs resistant epilepsy using individual and overall odds ratios (OR) with corresponding 95% confidence intervals (CIs) by Forest Plot (Comprehensive Meta-Analysis Version 3, USA). The <italic>P</italic>-value determined the significance of the combined ORs. If the <italic>P</italic>-value (<italic>P</italic>) < 0.05, we considered the pooled ORs statistically significant [<xref ref-type="bibr" rid="CR68">68</xref>]. The <italic>Z</italic>-value showed uniformisation of values and their position in the full distribution of values in the program. The <italic>I</italic><sup>2</sup> statistic test assessed statistical heterogeneity among included studies; if <italic>I</italic><sup>2</sup> < 50%, fixed-effects model pooled study data and if <italic>I</italic><sup>2</sup> ≥ 50%, random-effects model pooled it [<xref ref-type="bibr" rid="CR69">69</xref>]. Additionally, we performed subgroup analysis using genotype model to quantify the reported association between polymorphisms and AEDs resistant epilepsy in each reported genotypic model. To identify publication bias between the included studies, we applied Funnel plot and Egger’s regression tests. The graph of Funnel plot reflected publication bias. Egger’s test assessed and confirmed funnel plot’s results: <italic>P</italic> < 0.05 determined the existence of bias [<xref ref-type="bibr" rid="CR70">70</xref>].</p></sec></sec><sec id="Sec7"><title>Results</title><sec id="Sec8"><title>Evidence base</title><p>We identified a total of 640 potentially relevant articles. We excluded a total of 591 publications from the further analysis: abstract, articles showing absence of associations between polymorphisms and AEDs resistant epilepsy for insufficient data, case reports, duplicated articles, letter to the editors, meta-analysis, not epileptic studies, not human reports, researches about other treatments than AEDs, review articles and studies not related to associations between polymorphisms and AEDs resistant epilepsy (Fig. <xref rid="Fig1" ref-type="fig">1</xref>).<fig id="Fig1"><label>Fig. 1</label><caption><p>PRISMA flow diagram: study methodology of excluded and included articles</p></caption><graphic xlink:href="12883_2017_801_Fig1_HTML" id="MO1"></graphic></fig></p><p>Among the 49 reports that met eligibility requirements], 39 reviewed an association between polymorphisms and epilepsy drug resistance [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR37">37</xref>, <xref ref-type="bibr" rid="CR50">50</xref>, <xref ref-type="bibr" rid="CR51">51</xref>, <xref ref-type="bibr" rid="CR62">62</xref>, <xref ref-type="bibr" rid="CR71">71</xref>–<xref ref-type="bibr" rid="CR90">90</xref>]. We identified the majority of polymorphisms in AEDs transporter genes: <italic>ABCB1</italic> and <italic>ABCC2</italic>. We also found other polymorphisms in AEDs target genes: gamma-aminobutyric acid-a receptor alpha1-subunit (<italic>GABRA1</italic>), gamma-aminobutyric acid-a receptor alpha2-subunit (<italic>GABRA2</italic>), gamma-aminobutyric acid-a receptor alpha3-subunit (<italic>GABRA3</italic>), sodium channel nav1.1 (<italic>SCN1A</italic>), sodium channel nav1.2 (<italic>SCN2A</italic>), in other potential genes as apolipoprotein e (<italic>ApoE</italic>), cytochrome p450 1a1 (<italic>CYP1A1</italic>), cytochrome p450 family member 2c9 (<italic>CYP2C9</italic>), gamma-aminobutyric acid transporter 3 (<italic>GAT3</italic>), glutathione s-transferases mu 1 (<italic>GSTM1</italic>) and solute ligand carrier family 6 member a4 (<italic>SLC6A4</italic>). We summarized the characteristics of polymorphisms implicated in AEDs resistance in different ethnic groups (Table <xref rid="Tab1" ref-type="table">1</xref>). We excluded 10 full-text studies for insufficient data (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). Only 13 met the inclusion criteria and constituted the data set for this analysis [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR33">33</xref>–<xref ref-type="bibr" rid="CR36">36</xref>] (Table <xref rid="Tab2" ref-type="table">2</xref>).<table-wrap id="Tab1"><label>Table 1</label><caption><p>Characteristics of reviewed studies reporting associations between polymorphisms and AEDs resistance epilepsy</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Gene</th><th>Polymorphism</th><th>Genotype model</th><th>Ethnicity</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="25"><italic>ABCB1</italic></td><td>c.1199G > A<break></break>(rs2229109)</td><td>GA vs. GG</td><td>Mexican</td><td>Escalante-Santiago et al. 2014 [<xref ref-type="bibr" rid="CR71">71</xref>]</td></tr><tr><td>c.1236T > C<break></break>(rs1128503)</td><td>CC + CT vs. TT</td><td>Iranian</td><td>Maleki et al. 2010 [<xref ref-type="bibr" rid="CR72">72</xref>]</td></tr><tr><td rowspan="5">c.2677G > T/A<break></break>(rs2032582)</td><td>AT + AG vs. GG + GT + TT</td><td>Mexican</td><td>Escalante-Santiago et al. 2014 [<xref ref-type="bibr" rid="CR71">71</xref>]</td></tr><tr><td rowspan="2">TT vs. GG + GT</td><td>European</td><td>Sánchez et al. 2010 [<xref ref-type="bibr" rid="CR31">31</xref>]</td></tr><tr><td rowspan="2">Malaysian</td><td>Subenthiran et al. 2013 [<xref ref-type="bibr" rid="CR37">37</xref>]</td></tr><tr><td rowspan="2">TT vs. GG</td><td>Subenthiran et al. 2013 [<xref ref-type="bibr" rid="CR73">73</xref>]</td></tr><tr><td>Japanese</td><td>Seo et al. 2006 [<xref ref-type="bibr" rid="CR36">36</xref>]</td></tr><tr><td rowspan="18">c.3435C > T<break></break>(rs1045642)</td><td rowspan="8">CC vs. TT</td><td rowspan="2">Chinese</td><td>Hung et al. 2005 [<xref ref-type="bibr" rid="CR22">22</xref>]</td></tr><tr><td>Hung et al. 2007 [<xref ref-type="bibr" rid="CR23">23</xref>]</td></tr><tr><td>Egyptian</td><td>Ebid et al. 2007 [<xref ref-type="bibr" rid="CR24">24</xref>]</td></tr><tr><td rowspan="2">European</td><td>Sánchez et al. 2010 [<xref ref-type="bibr" rid="CR31">31</xref>]</td></tr><tr><td>Siddiqui et al. 2003 [<xref ref-type="bibr" rid="CR25">25</xref>]</td></tr><tr><td></td><td>Stasiołek et al. 2016 [<xref ref-type="bibr" rid="CR26">26</xref>]</td></tr><tr><td>Indian</td><td>Taur et al. 2014 [<xref ref-type="bibr" rid="CR27">27</xref>]</td></tr><tr><td>Iranian</td><td>Sayyah et al. 2011 [<xref ref-type="bibr" rid="CR28">28</xref>]</td></tr><tr><td></td><td>Thai</td><td>Keangpraphun et al. 2015 [<xref ref-type="bibr" rid="CR29">29</xref>]</td></tr><tr><td rowspan="2">CC vs. CT + TT</td><td rowspan="3">European</td><td>Basic et al. 2008 [<xref ref-type="bibr" rid="CR30">30</xref>]</td></tr><tr><td>Sánchez et al. 2010 [<xref ref-type="bibr" rid="CR31">31</xref>]</td></tr><tr><td>CC + CT vs. TT</td><td>Soranzo et al. 2004 [<xref ref-type="bibr" rid="CR32">32</xref>]</td></tr><tr><td>CT vs. CC + TT</td><td>Iranian</td><td>Sayyah et al. 2011 [<xref ref-type="bibr" rid="CR28">28</xref>]</td></tr><tr><td rowspan="4">TT vs. CC</td><td>Australian</td><td>Tan et al. 2004 [<xref ref-type="bibr" rid="CR33">33</xref>]</td></tr><tr><td>Chinese</td><td>Kwan et al. 2007 [<xref ref-type="bibr" rid="CR34">34</xref>]</td></tr><tr><td>Indian</td><td>Shaheen et al. 2014 [<xref ref-type="bibr" rid="CR35">35</xref>]</td></tr><tr><td>Japanese</td><td>Seo et al. 2006 [<xref ref-type="bibr" rid="CR36">36</xref>]</td></tr><tr><td>TT vs. CT + CC</td><td>Malaysian</td><td>Subenthiran et al. 2013 [<xref ref-type="bibr" rid="CR37">37</xref>]</td></tr><tr><td rowspan="13"><italic>ABCC2</italic></td><td>c.-24C > T (rs717620)</td><td>CT + TT vs. CC</td><td>Chinese</td><td>Qu et al. 2012 [<xref ref-type="bibr" rid="CR74">74</xref>]</td></tr><tr><td>c.-1019A > G<break></break>(rs2804402)</td><td>AA vs. AG + GG</td><td rowspan="2">Indian</td><td rowspan="2">Grover et al. 2012 [<xref ref-type="bibr" rid="CR75">75</xref>]</td></tr><tr><td>c.-1549G > A<break></break>(rs1885301)</td><td>GG vs. GA + AA</td></tr><tr><td rowspan="6">c.1249G > A<break></break>(rs2273697)</td><td rowspan="3">AA vs. GG</td><td>Malaysian</td><td rowspan="5">Sha’ari et al. 2014 [<xref ref-type="bibr" rid="CR50">50</xref>]</td></tr><tr><td>Japanese</td></tr><tr><td rowspan="4">Chinese</td></tr><tr><td>GA vs. GG</td></tr><tr><td>GA + AA vs. GG</td></tr><tr><td>GA vs. GG + AA</td><td>Ma et al. 2014 [<xref ref-type="bibr" rid="CR51">51</xref>]</td></tr><tr><td rowspan="4">c.3972C > T (rs3740066)</td><td rowspan="2">CT vs. CC<break></break>CC + TT vs. CC</td><td>Malaysian</td><td rowspan="2">Sha’ari et al. 2014 [<xref ref-type="bibr" rid="CR50">50</xref>]</td></tr><tr><td rowspan="2">Chinese</td></tr><tr><td>CT + TT vs. CC</td><td>Qu et al. 2012 [<xref ref-type="bibr" rid="CR74">74</xref>]</td></tr><tr><td>TT vs. CC + CT</td><td>Mexican</td><td>Escalante-Santiago et al. 2014 [<xref ref-type="bibr" rid="CR71">71</xref>]</td></tr><tr><td rowspan="2"><italic>ApoE</italic></td><td>c.388T > C<break></break>(rs429358),<break></break>c.526C > T<break></break>(rs7412)</td><td>e3/4 vs. e3/3 + e2/3</td><td>European</td><td>Sporiš et al. 2005 [<xref ref-type="bibr" rid="CR76">76</xref>]</td></tr><tr><td>c.388T > C<break></break>(rs429358)</td><td>e4 vs. e2 + e3</td><td>Chinese</td><td>Gong et al. 2016 [<xref ref-type="bibr" rid="CR77">77</xref>]</td></tr><tr><td><italic>CYP1A1</italic></td><td>IVS1 + 606C > A<break></break>(rs2606345)</td><td>CC + CA vs. AA<break></break>CC vs. CA + AA</td><td>Indian</td><td>Grover et al. 2010 [<xref ref-type="bibr" rid="CR78">78</xref>]</td></tr><tr><td><italic>CYP2C9</italic></td><td>c.1075A > C<break></break>(rs1057910)</td><td>CYP2C9*3/*3 vs. CYP2C9*1/*1+<break></break>CYP2C9*1/*3</td><td>European</td><td>Seven et al. 2014 [<xref ref-type="bibr" rid="CR79">79</xref>]</td></tr><tr><td rowspan="3"><italic>GABRA1</italic></td><td rowspan="2">IVS11 + 15A > G<break></break>(rs2279020)</td><td rowspan="2">GG vs. AA + AG</td><td rowspan="2">Indian</td><td>Kumari et al. 2010 [<xref ref-type="bibr" rid="CR80">80</xref>]</td></tr><tr><td>Kumari et al. 2011 [<xref ref-type="bibr" rid="CR81">81</xref>]</td></tr><tr><td>c.74 + 448C > T (rs6883877)</td><td>CC vs. TC + TT</td><td rowspan="3">Thai</td><td rowspan="3">Hung et al. 2013 [<xref ref-type="bibr" rid="CR82">82</xref>]</td></tr><tr><td><italic>GABRA2</italic></td><td>g.46240004A > G<break></break>(rs511310)</td><td>GG vs. AA + AG</td></tr><tr><td><italic>GABRA3</italic></td><td>c.-27 + 37622A > G<break></break>(rs4828696)</td><td>TT vs. CC + CT</td></tr><tr><td><italic>GAT3</italic></td><td>c.1572C > T<break></break>(rs2272400)</td><td>CT + TT vs. CC</td><td>Korean</td><td>Kim et al. 2011 [<xref ref-type="bibr" rid="CR83">83</xref>]</td></tr><tr><td><italic>GSTM1</italic></td><td>GSTM1*0</td><td>GSTM1- vs. GSTM1+</td><td rowspan="3">Chinese</td><td>Liu et al. 2002 [<xref ref-type="bibr" rid="CR84">84</xref>]</td></tr><tr><td rowspan="5"><italic>SCN1A</italic></td><td rowspan="3">c.3184A > G<break></break>(rs2298771)</td><td>AA vs. AG + GG</td><td>Wang et al. 2014 [<xref ref-type="bibr" rid="CR85">85</xref>]</td></tr><tr><td>AG + GG vs. AA</td><td>Zhou et al. 2012 [<xref ref-type="bibr" rid="CR86">86</xref>]</td></tr><tr><td>AG vs. AA + GG</td><td>Egyptian</td><td>Abo El Fotoh et al. 2016 [<xref ref-type="bibr" rid="CR87">87</xref>]</td></tr><tr><td rowspan="2">IVS5-91G > A<break></break>(rs3812718)</td><td rowspan="2">AA vs. AG + GG</td><td rowspan="2">Japanese</td><td>Ma et al. 2014 [<xref ref-type="bibr" rid="CR51">51</xref>]</td></tr><tr><td>Abe et al. 2008 [<xref ref-type="bibr" rid="CR62">62</xref>]</td></tr><tr><td><italic>SCN2A</italic></td><td>IVS7-32A > G<break></break>(rs2304016)</td><td>AA vs. AG + GG</td><td>Chinese</td><td>Kwan et al. 2008 [<xref ref-type="bibr" rid="CR88">88</xref>]</td></tr><tr><td rowspan="3"><italic>SLC6A4</italic></td><td>5-HTTLPR</td><td>L/L vs. S/L + S/S</td><td>European</td><td>Hecimovic et al. 2010 [<xref ref-type="bibr" rid="CR89">89</xref>]</td></tr><tr><td rowspan="2">STin2 VNTR</td><td>12/12 vs. 10/10</td><td>Argentinean</td><td>Kauffman et al. 2009 [<xref ref-type="bibr" rid="CR90">90</xref>]</td></tr><tr><td>12/12 vs. 10/12 + 10/10</td><td>European</td><td>Hecimovic et al. 2010 [<xref ref-type="bibr" rid="CR89">89</xref>]</td></tr></tbody></table><table-wrap-foot><p><italic>Abbreviation: ABCB1</italic> atp-binding cassette sub-family b member 1, <italic>ABCC2</italic> atp-binding cassette subfamily c member 2, <italic>ApoE</italic> apolipoprotein e, <italic>CYP1A1</italic> cytochrome p450 1a1, <italic>CYP2C9</italic> cytochrome p450 family member 2c9, <italic>GABRA1</italic> gamma-aminobutyric acid-a receptor alpha1-subunit, <italic>GABRA2</italic> gamma-aminobutyric acid-a receptor alpha2-subunit, <italic>GABRA3</italic> gamma-aminobutyric acid-a receptor alpha3-subunit, <italic>GAT3</italic> gamma-aminobutyric acid transporter 3, <italic>GSTM1</italic> glutathione s-transferases mu 1, <italic>SCN1A</italic> sodium channel nav1.1, <italic>SCN2A</italic> sodium channel nav1.2, <italic>SLC6A4</italic> solute ligand carrier family 6 member a4</p></table-wrap-foot></table-wrap><table-wrap id="Tab2"><label>Table 2</label><caption><p>Summary of studies included into meta-analysis</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Polymorphism</th><th>Genotype Model</th><th>Ethnicity</th><th colspan="2">Total No.</th><th>Male %/Female %</th><th>Mean Age (years)</th><th>Aetiology of epilepsy</th><th>Type of epilepsy</th><th>AEDs</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="20"><italic>ABCB1</italic><break></break>c.3435C>T</td><td rowspan="20">CC vs. TT</td><td rowspan="6">Chinese</td><td rowspan="2">Cases</td><td rowspan="2">331</td><td rowspan="2">56.193/43.807</td><td>39.1±11 <sup>a</sup></td><td>Cryptogenic</td><td rowspan="2">Generalized, partial</td><td rowspan="2">–</td><td rowspan="3">Hung et al., 2005 [<xref ref-type="bibr" rid="CR22">22</xref>]</td></tr><tr><td>38.5±13.4 <sup>b</sup></td><td>Cryptogenic, idiopathic</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Cases</td><td rowspan="2">331</td><td rowspan="2">–</td><td>40.11±11 <sup>a</sup></td><td>Cryptogenic</td><td>Generalized, partial</td><td rowspan="2">CBZ, CNZ, GBP, LTG, OXC, PB, PHT, TPM, VGB, VPA</td><td rowspan="3">Hung et al., 2007 [<xref ref-type="bibr" rid="CR23">23</xref>]</td></tr><tr><td>39.5±13.4 <sup>b</sup></td><td>Cryptogenic, idiopathic</td><td></td></tr><tr><td>Controls</td><td>287</td><td>–</td><td>41±10.9</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Egyptian</td><td>Cases</td><td>100</td><td>56 /44</td><td>35.9 ±8.42</td><td>–</td><td>Generalized, partial</td><td>PHT <sup>a</sup></td><td rowspan="2">Ebid et al., 2007 [<xref ref-type="bibr" rid="CR24">24</xref>]</td></tr><tr><td>Controls</td><td>50</td><td>64/36</td><td>38.6±10.32</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="6">European</td><td>Cases</td><td>289</td><td>49.827/50.173</td><td>27.0 ±18.5 <sup>a</sup><break></break>26.0 ±19.8 <sup>b</sup></td><td>Various <sup>d</sup></td><td>Generalized, partial</td><td>–</td><td rowspan="2">Sánchez et al., 2010 [<xref ref-type="bibr" rid="CR31">31</xref>]</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Cases</td><td>315</td><td>–</td><td>–</td><td>–</td><td>Generalized, partial</td><td>–</td><td rowspan="2">Siddiqui et al., 2003 [<xref ref-type="bibr" rid="CR25">25</xref>]</td></tr><tr><td>Controls</td><td>200</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td>Cases</td><td>173</td><td>50.289/49.711</td><td>8.5±4.84 <sup>a</sup><break></break>8.2±4.019 <sup>b</sup></td><td>–</td><td>–</td><td>CBZ, GBP, LEV, LTG,<break></break>OXC, TPM</td><td rowspan="2">Stasiołek et al., 2016 [<xref ref-type="bibr" rid="CR26">26</xref>]</td></tr><tr><td>Controls</td><td>98</td><td>53.061/46.939</td><td>8.3±4.64</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Indian</td><td>Cases</td><td>115</td><td>73.215/26.786</td><td>34.69±10.06 <sup>a</sup><break></break>38.02±11.46 <sup>b</sup></td><td>–</td><td>–</td><td>CBZ, PB, PHT</td><td rowspan="2">Taur et al., 2014 [<xref ref-type="bibr" rid="CR27">27</xref>]</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Iranian</td><td>Cases</td><td>332</td><td>52.711/47.289</td><td>28.8±11 <sup>a</sup><break></break>27±13 <sup>b</sup></td><td>Various <sup>d</sup></td><td>Generalized, partial</td><td>CBZ, CNZ, LEV, LTG, OXC, PB, PHT, PRI, TPM, VPA</td><td rowspan="2">Sayyah et al., 2011 [<xref ref-type="bibr" rid="CR28">28</xref>]</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Thai</td><td>Cases</td><td>110</td><td>52.727/47.273</td><td>41.96 ±12.19 <sup>a</sup><break></break>46.65±12.65 <sup>b</sup></td><td>–</td><td>Generalized, partial</td><td>CBZ, PB, PHT, VPA</td><td rowspan="2">Keangpraphun et al., 2015 [<xref ref-type="bibr" rid="CR29">29</xref>]</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="8"><italic>ABCB1</italic><break></break>c.3435C>T</td><td rowspan="8">TT vs. CC</td><td rowspan="2">Australian</td><td>Cases</td><td>609</td><td>–</td><td>–</td><td>–</td><td>Generalized, partial</td><td>–</td><td rowspan="2">Tan et al., 2004 [<xref ref-type="bibr" rid="CR33">33</xref>]</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Chinese</td><td>Cases</td><td>746</td><td>–</td><td>–</td><td>Various <sup>d</sup></td><td>–</td><td>–</td><td rowspan="2">Kwan et al., 2007 [<xref ref-type="bibr" rid="CR34">34</xref>]</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Indian</td><td>Cases</td><td>220</td><td>65.455/34.545</td><td>8.1±2.47 <sup>e</sup><break></break>38.3±12.2 <sup>f</sup></td><td>Various <sup>d</sup></td><td>Generalized, partial</td><td>CBZ, CLB, LEV, OXC, PHT, VPA</td><td rowspan="2">Shaheen et al., 2013 [<xref ref-type="bibr" rid="CR35">35</xref>]</td></tr><tr><td>Controls</td><td>220</td><td>65.455/34.545</td><td>10.5±4.5 <sup>e</sup><break></break>37±10 <sup>f</sup></td><td>–</td><td>–</td><td>–</td></tr><tr><td rowspan="2">Japanese</td><td>Cases</td><td>210</td><td>56.667/43.333</td><td>18.0±9.6 <sup>a</sup><break></break>16.5±9.5 <sup>b</sup></td><td>Various <sup>d</sup></td><td>Generalized, partial</td><td>AZA, CBZ, CLB, CNZ, DZP, ESM, Ethotoin, NTZ, PB, PHT, VPA, ZNS</td><td rowspan="2">Seo et al., 2006 [<xref ref-type="bibr" rid="CR36">36</xref>]</td></tr><tr><td>Controls</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td><td>–</td></tr></tbody></table><table-wrap-foot><p><italic>Abbreviation</italic>: <italic>AEDs</italic> anti-epileptic drugs, <italic>ABCB1</italic> atp-binding cassette sub-family b member 1, <italic>AZA</italic> acetazolamide, <italic>CBZ</italic> carbamazepine, <italic>CLB</italic> clobazam, <italic>CNZ</italic> clonazepam, <italic>DZP</italic> diazepam, <italic>ESM</italic> ethosuximide, <italic>GBP</italic> gabapentin, <italic>LEV</italic> levetiracetam, <italic>LTG</italic> lamotrigine, <italic>NTZ</italic> nitrozepam, <italic>OXC</italic> oxcarbazepine, <italic>PB</italic> phenobarbital, <italic>PHT</italic> phenytoin, <italic>PRI</italic> primidone, <italic>TPM</italic> topiramate, <italic>VGB</italic> vigabatrin, <italic>VPA</italic> valproate, <italic>ZNS</italic> zonisamide, − = no data, <sup>a</sup> AEDs-resistant cases, <sup>b</sup> AEDs-responsive cases, <sup>c</sup> Administration of PHT as monotherapy or polytherapy was not mentioned, <sup>d</sup> Idiopathic, cryptogenic, symptomatic, <sup>e</sup> <15 years, <sup>f</sup> >15 years</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec9"><title>Data analysis</title><p>We carried out a meta-analysis to evaluate the relationship between <italic>ABCB1</italic> C3435T polymorphism and AEDs resistance among AEDs-resistant patients vs. AEDs-responsive patients. The included studies were heterogeneous for the study characteristics. The analysis of data showed that 454 of 1653 AEDs-resistant patients (27.465%) and 282 of 1732 AEDs-responsive patients (16.282%) were included in the statistical analysis [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR33">33</xref>–<xref ref-type="bibr" rid="CR36">36</xref>]. The frequency of AEDs-resistant cases was higher than AEDs-responsive patients. We divided the age of cases and controls into three subgroups: >20 years, 20–40 years, and <40 years. We divided the gender of cases and controls into two subgroups: males >50% and males <50%. A total of eight included studies were conducted in Asia [<xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR27">27</xref>–<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR34">34</xref>–<xref ref-type="bibr" rid="CR36">36</xref>], three studies in Europe [<xref ref-type="bibr" rid="CR25">25</xref>, <xref ref-type="bibr" rid="CR26">26</xref>, <xref ref-type="bibr" rid="CR31">31</xref>], one study in Egypt [<xref ref-type="bibr" rid="CR24">24</xref>] and one another in Australia [<xref ref-type="bibr" rid="CR33">33</xref>]. We classified the cases by epilepsy syndrome (idiopathic, cryptogenic or symptomatic epilepsy) [<xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR34">34</xref>, <xref ref-type="bibr" rid="CR36">36</xref>] or by seizure types (generalized or partial seizures) [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR24">24</xref>, <xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR33">33</xref>, <xref ref-type="bibr" rid="CR35">35</xref>, <xref ref-type="bibr" rid="CR36">36</xref>]. However, the classifications of cases by epilepsy syndrome were not mentioned in seven studies [<xref ref-type="bibr" rid="CR24">24</xref>–<xref ref-type="bibr" rid="CR27">27</xref>, <xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR33">33</xref>, <xref ref-type="bibr" rid="CR35">35</xref>] and the classifications of cases by seizure types were not mentioned in three studies [<xref ref-type="bibr" rid="CR26">26</xref>, <xref ref-type="bibr" rid="CR27">27</xref>, <xref ref-type="bibr" rid="CR34">34</xref>]. Two studies were stratified by epilepsy syndrome [<xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR31">31</xref>] and three studies were stratified by seizure types [<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR33">33</xref>, <xref ref-type="bibr" rid="CR35">35</xref>]. Cases were treated with AEDs polytherapy in seven studies [<xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR26">26</xref>–<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR35">35</xref>, <xref ref-type="bibr" rid="CR36">36</xref>]. Only one study reported association between <italic>ABCB1</italic> C3435T polymorphism and cases with Phenytoin (PHT) therapy, the administration of PHT as monotherapy or polytherapy was not mentioned [<xref ref-type="bibr" rid="CR24">24</xref>]. However, AEDs were not specified in five studies [<xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR25">25</xref>, <xref ref-type="bibr" rid="CR27">27</xref>, <xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR33">33</xref>]. We summarized the characteristics of the available included studies in Table <xref rid="Tab2" ref-type="table">2</xref>.</p></sec><sec id="Sec10"><title>Association of <italic>ABCB1</italic> C3435T polymorphism with the susceptibility to AEDs resistance</title><p>The heterogeneity among the included studies was high (<italic>I</italic><sup>2</sup> = 82.961%, <italic>P</italic> < 10<sup>-3</sup>) and we used a random-effects model [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR33">33</xref>–<xref ref-type="bibr" rid="CR36">36</xref>]. The summary OR was 1.877, 95% CI 1.213–2.905, <italic>P</italic> = 0.005 showing that <italic>ABCB1</italic> C3435T was significantly associated with AEDs resistance (Fig. <xref rid="Fig2" ref-type="fig">2</xref>).<fig id="Fig2"><label>Fig. 2</label><caption><p>Association between <italic>ABCB1</italic> C3435T polymorphism and AEDs resistant epilepsy. Forest plot showed individual and overall ORs (black squares) with corresponding 95% CIs (horizontal bars) by individual report. <italic>P</italic>-value showed statistical significance of ORs and <italic>Z</italic>-value showed uniformisation of values and its position in the full distribution of values. Heterogeneity between the studies was mentioned</p></caption><graphic xlink:href="12883_2017_801_Fig2_HTML" id="MO2"></graphic></fig></p><p>For the robustness of our findings, we used subanalysis by dominant (CC vs. TT) and recessive (TT vs. CC) genotype models. The heterogeneity among the nine included studies was high (<italic>I</italic><sup>2</sup> = 87.843%, <italic>P</italic> < 10<sup>-3</sup>) in the dominant model [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR31">31</xref>]. The summary OR was 1.686, 95% CI 0.877–3.242, <italic>P</italic> = 0.117 under a random-effects model (Fig. <xref rid="Fig3" ref-type="fig">3</xref>). The analysis of the recessive model revealed that the heterogeneity was absent (<italic>I</italic><sup>2</sup> = 0.000%, <italic>P</italic> = 0.727) among the four included studies [<xref ref-type="bibr" rid="CR33">33</xref>–<xref ref-type="bibr" rid="CR36">36</xref>]. The summary OR was 2.375, 95% CI 1.775–3178, <italic>P</italic> < 10<sup>-3</sup> under a fixed-effects model (Fig. <xref rid="Fig4" ref-type="fig">4</xref>). Therefore, the results of our present meta-analysis indicates that the association of <italic>ABCB1</italic> C3435T polymorphism with the risk of AEDs resistance, exists and it is more significant in <italic>ABCB1</italic> 3435TT genotype than in 3435CC genotype.<fig id="Fig3"><label>Fig. 3</label><caption><p>Association between <italic>ABCB1</italic> 3435CC genotype and AEDs resistant epilepsy. Forest plot showed individual and overall ORs (black squares) with corresponding 95% CIs (horizontal bars) by individual report. <italic>P</italic>-value showed statistical significance of ORs and <italic>Z</italic>-value showed uniformisation of values and its position in the full distribution of values. Heterogeneity between the studies was mentioned</p></caption><graphic xlink:href="12883_2017_801_Fig3_HTML" id="MO3"></graphic></fig><fig id="Fig4"><label>Fig. 4</label><caption><p>Association between <italic>ABCB1</italic> 3435TT genotype and AEDs resistant epilepsy. Forest plot showed individual and overall ORs (black squares) with corresponding 95% CIs (horizontal bars) by individual report. <italic>P</italic>-value showed statistical significance of ORs and <italic>Z</italic>-value showed uniformisation of values and its position in the full distribution of values. Heterogeneity between the studies was mentioned</p></caption><graphic xlink:href="12883_2017_801_Fig4_HTML" id="MO4"></graphic></fig></p></sec><sec id="Sec11"><title>Analysis of publication bias</title><p>For the association between <italic>ABCB1</italic> C3435T polymorphism, <italic>ABCB1</italic> 3435CC, and 3435TT genotype models with AEDs resistance, Funnel Plot showed asymmetrical appearances (Figs. <xref rid="Fig5" ref-type="fig">5</xref>, <xref rid="Fig6" ref-type="fig">6</xref> and <xref rid="Fig7" ref-type="fig">7</xref>) and Egger’s regression test showed that <italic>P</italic> = 0.413, <italic>P</italic> = 0.492, and <italic>P</italic> = 0.085, respectively, were more than 0.05. The two tests demonstrated a significant publication bias.<fig id="Fig5"><label>Fig. 5</label><caption><p>Publication bias of the association between <italic>ABCB1</italic> C3435T polymorphism and AEDs resistant epilepsy</p></caption><graphic xlink:href="12883_2017_801_Fig5_HTML" id="MO5"></graphic></fig><fig id="Fig6"><label>Fig. 6</label><caption><p>Publication bias of the association between <italic>ABCB1</italic> 3435CC genotype model and AEDs resistant epilepsy</p></caption><graphic xlink:href="12883_2017_801_Fig6_HTML" id="MO6"></graphic></fig><fig id="Fig7"><label>Fig. 7</label><caption><p>Publication bias of the association between <italic>ABCB1</italic> 3435TT genotype model and AEDs resistant epilepsy</p></caption><graphic xlink:href="12883_2017_801_Fig7_HTML" id="MO7"></graphic></fig></p></sec></sec><sec id="Sec12"><title>Discussion</title><p>Epilepsy is a serious health problem affecting about 65 million people worldwide and manifesting many syndromes and types of seizures [<xref ref-type="bibr" rid="CR60">60</xref>]. Since uncontrollable seizures increase morbidity and mortality, drug-resistant epilepsy is one of the major problems that physicians encounter. Recurrent seizures can devastate patients and their families. Therefore, drug-resistant epilepsy still remains one of the main challenges for epileptologists.</p><p>Since that genetic polymorphisms may play a role in response to AEDs [<xref ref-type="bibr" rid="CR10">10</xref>], we conducted an updated systematic review in order to summarize the impact of polymorphisms in <italic>ABCB1</italic>, <italic>ABCC2</italic>, <italic>ApoE</italic>, <italic>CYP1A1</italic>, <italic>CYP2C9</italic>, <italic>GABRA1</italic>, <italic>GABRA2</italic>, <italic>GABRA3</italic>, <italic>GAT3</italic>, <italic>GSTM1</italic>, <italic>SCN1A</italic>, <italic>SCN2A</italic>, and <italic>SLC6A4</italic> genes on AEDs resistant epilepsy. Our meta-analysis concerned only the association between <italic>ABCB1</italic> C3435T polymorphism and drug-resistant epilepsy, which revealed a significant risk to pharmacoresistance (OR = 1.877, 95% CI 1.213–2.905, <italic>P</italic> = 0.005) (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). Some studies confirmed our results [<xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR37">37</xref>]. Nevertheless, many other reports failed to prove an association between <italic>ABCB1</italic> C3435T polymorphism and refractory epilepsy [<xref ref-type="bibr" rid="CR38">38</xref>–<xref ref-type="bibr" rid="CR42">42</xref>, <xref ref-type="bibr" rid="CR91">91</xref>–<xref ref-type="bibr" rid="CR96">96</xref>].</p><p>The first publication showed that drug-resistant patients compared to drug-responsive patients, were more likely to have the CC genotype than the TT genotype (<italic>P</italic> = 0.006) [<xref ref-type="bibr" rid="CR25">25</xref>]. Zimprich et al. confirmed the result [<xref ref-type="bibr" rid="CR97">97</xref>]. Moreover, many studies indicated that the CC genotype were more prevalent in drug-resistant epilepsy [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR16">16</xref>–<xref ref-type="bibr" rid="CR23">23</xref>]. However, three Asian studies [<xref ref-type="bibr" rid="CR34">34</xref>–<xref ref-type="bibr" rid="CR36">36</xref>] and one Australian study [<xref ref-type="bibr" rid="CR33">33</xref>] showed the opposite association of TT genotype high frequency. In addition, our meta-analysis showed that patients resistant to AEDs were more likely to have <italic>ABCB1</italic> 3435TT genotype (OR = 2.375, 95% CI 1.775–3.178, <italic>P</italic> < 10<sup>-3</sup>) than 3435CC genotype (OR = 1.686, 95% CI 0.877–3.242, <italic>P</italic> = 0.117) (Figs. <xref rid="Fig3" ref-type="fig">3</xref> and <xref rid="Fig4" ref-type="fig">4</xref>).</p><p>Due to these controversial results, meta-analyses were made in order to clarify the association between <italic>ABCB1</italic> C3435T polymorphism and drug-resistant epilepsy. The majority suggest that the <italic>ABCB1</italic> C3435T polymorphism may not be involved in the response to AEDs [<xref ref-type="bibr" rid="CR58">58</xref>–<xref ref-type="bibr" rid="CR62">62</xref>]. The study of Bournissen et al. showed no association of <italic>ABCB1</italic> C3435T polymorphism with risk of drug resistance in overall and in the subgroup analysis by ethnicity (Asian and Caucasian populations) (<italic>n</italic> = 3371 subjects) [<xref ref-type="bibr" rid="CR43">43</xref>]. The first study of Haerian et al. demonstrated the lack of allelic association with the risk of drug resistance under fixed and random effects models (<italic>n</italic> = 6755 subjects) [<xref ref-type="bibr" rid="CR44">44</xref>] and the second study of Haerian et al. showed no significant association of <italic>ABCB1</italic> alleles, genotypes, and haplotypes with recurrent seizures (<italic>n</italic> = 7067 patients) [<xref ref-type="bibr" rid="CR45">45</xref>]. In the two studies, subanalysis of studies by ethnicity (Asian and Caucasian populations) yielded similar findings. Nurmohamed et al. failed to find a statistical significance between genotypes of <italic>ABCB1</italic> C3435T polymorphism in cases and controls (<italic>n</italic> = 3996 subjects) [<xref ref-type="bibr" rid="CR46">46</xref>]. No allelic neither genotypic association of <italic>ABCB1</italic> C3435T polymorphism with childhood risk of drug resistance was found in overall and in the subgroup analysis by ethnicity (Asian and Caucasian populations) (<italic>n</italic> = 1249 subjects) in the study of Sun et al. [<xref ref-type="bibr" rid="CR47">47</xref>]. Recently, two meta-analyses have indicated that CC genotype was associated with recurrent seizures in Caucasians. However, none of the genetic comparisons exhibited a significant association in Asians [<xref ref-type="bibr" rid="CR63">63</xref>, <xref ref-type="bibr" rid="CR64">64</xref>]. In our knowledge, no another meta-analysis showed the same result as ours. Overall, meta-analyses stratified by genotype genetic models in the overall studies, indicate that the polymorphism may not play a major role in drug resistance to AEDs [<xref ref-type="bibr" rid="CR46">46</xref>] and similar results are found in the subgroup analysis for the Asian and the Caucasian populations [<xref ref-type="bibr" rid="CR43">43</xref>–<xref ref-type="bibr" rid="CR45">45</xref>, <xref ref-type="bibr" rid="CR47">47</xref>]. However, other meta-analyses show a significant association in a specific ethnic subgroup [<xref ref-type="bibr" rid="CR63">63</xref>, <xref ref-type="bibr" rid="CR64">64</xref>]. These discrepant results are mainly due to the small sample size, which is a common problem in association studies leading to underpowered genotypic results. Worldwide collaboration between different centers is then necessary to increase the sample size. In addition, ethnicity is another factor that may affect the results. An allele may become more common in ethnic subgroup but not in another, which may affect the response to AEDs [<xref ref-type="bibr" rid="CR45">45</xref>]. However, four meta-analyses show no evidence that the <italic>ABCB1</italic> C3435T polymorphism is associated with the risk of resistance to AEDs in Asians and Caucasians [<xref ref-type="bibr" rid="CR43">43</xref>–<xref ref-type="bibr" rid="CR45">45</xref>, <xref ref-type="bibr" rid="CR47">47</xref>]. Therefore, meta-analysis startified by ethnicity are needed to increase in order to confirm the ethnic-dependence of AEDs resistant epilepsy.</p><p>AEDs transporters have contribute in pharmacoresistant epilepsy. In fact, the most studied AEDs transporter proteins like membrane proteins, are ABC transporter superfamily members. They are ATP-dependent drug efflux pumps for specific AED and are mainly encoded by <italic>ABCB1</italic> gene. ABCB1 protein or P-gp was transporte AED in the BBB [<xref ref-type="bibr" rid="CR72">72</xref>]. P-gp activity can be affected by <italic>ABCB1</italic> polymorphisms reducing plasmatic levels of AEDs and minimizing antiepileptic treatment efficiency in epileptic patients [<xref ref-type="bibr" rid="CR98">98</xref>, <xref ref-type="bibr" rid="CR99">99</xref>]. If genetic background affects the expression of P-gp, then penetration of AEDs in the brain might depend on the patient’s genotype [<xref ref-type="bibr" rid="CR16">16</xref>, <xref ref-type="bibr" rid="CR18">18</xref>]. Homozygous TT genotype is associated with decreased P-gp expression [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR100">100</xref>].</p><p>Compared to literature search supporting conflicting results, our results show a higher contribution of <italic>ABCB1</italic> 3435TT genotype on response to AEDs. Our findings may contribute to exhibit the implication of genetic markers in refractory epilepsy before starting the treatment. In order to have a better AEDs therapeutic response, the identification of new potential genetic markers become necessary against pharmcoresistance in epilepsy. This will lead to a better understanding of drug resistance mechanisms in epilepsy. Furthermore, it will be extremely important for individual AEDs selection, early surgery feasibility and development of new efficacious treatments.</p><sec id="Sec13"><title>Limitations</title><p>Our analysis is consistent to our strategy search, inclusion criteria and statistical parameters. However, it may be limited due to several factors: 1) Few number of included studies is insufficient to carry out a subgroup analysis by ethnicity. In addition, the ethnicities in the included studies are heterogeneous. PGt and PGx studies of AEDs resistance should be performed by ethnicity. 2) Publication bias and heterogeneity might have an impact on the meta-analysis results. 3) Most of the included studies match different types of epilepsy with different AEDs. The affinity of each AED for ABC transporters is variable. In fact, Valproic acid (VPA) is a widely used AED and it is not transported by P-gp [<xref ref-type="bibr" rid="CR101">101</xref>]. Thereby, the association between <italic>ABCB1</italic> C3435T polymorphism and drug resistance epilepsy could be affected. Correlation between PGt and PGx results with specific AED should be required. 4) Different inclusion criteria are used to classify AEDs-resistant patients in the included studies, subsequently, the interpretation of the meta-analysis results become very complex. In fact, AEDs-resistant patients were defined as patients who had at least one seizure per month or 10 seizures over the previous year, despite two or more AEDs at therapeutic dosages and/or serum drug concentrations in three studies [<xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR34">34</xref>]. In other reports, drug resistance was defined as the occurrence of at least four seizures over the year despite more than three appropriate and tolerated AEDs for the epilepsy syndrome [<xref ref-type="bibr" rid="CR25">25</xref>, <xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR33">33</xref>]. In some studies, it was defined as the failure of two appropriate and tolerated AEDs trials [<xref ref-type="bibr" rid="CR27">27</xref>, <xref ref-type="bibr" rid="CR29">29</xref>], with a poor clinical outcome and recurrent seizures [<xref ref-type="bibr" rid="CR35">35</xref>], or the occurrence of any types of seizures for a minimum of one year at the same dose of AEDs [<xref ref-type="bibr" rid="CR36">36</xref>], or any seizures during the past three months [<xref ref-type="bibr" rid="CR24">24</xref>] and more than 10 seizures over the year [<xref ref-type="bibr" rid="CR23">23</xref>].</p></sec></sec><sec id="Sec14"><title>Conclusions</title><p>Various studies have yielded contradictory findings regarding the relationship between <italic>ABCB1</italic> C3435T polymorphism and AEDs resistance in epilepsy. In the current meta-analysis, we demonstrate the existence of a statistical significant association between <italic>ABCB1</italic> 3435TT genotype and refractory epilepsy. Therefore, the screening of <italic>ABCB1</italic> gene for this polymorphism in the future might be useful to decide the best treatment option for each patient and to predict the treatment outcome for new epileptic patients. However, considering the few number of included studies and the significant publication bias found in this meta-analysis, further investigations should be helpful to validate the use of this polymorphism in treatment decisions.</p></sec></body><back><glossary><title>Abbreviations</title><def-list><def-item><term>ABC</term><def><p>atp-binding cassette</p></def></def-item><def-item><term><italic>ABCB1</italic></term><def><p>atp-binding cassette sub-family b member 1</p></def></def-item><def-item><term><italic>ABCC2</italic></term><def><p>atp-binding cassette sub-family c member 2</p></def></def-item><def-item><term>AEDs</term><def><p>Antiepileptic drugs</p></def></def-item><def-item><term><italic>ApoE</italic></term><def><p>Apolipoprotein e</p></def></def-item><def-item><term>BBB</term><def><p>Blood–brain barrier</p></def></def-item><def-item><term>CBZ</term><def><p>Carbamazepine</p></def></def-item><def-item><term>CIs</term><def><p>Confidence intervals</p></def></def-item><def-item><term><italic>CYP1A1</italic></term><def><p>Cytochrome p450 1a1</p></def></def-item><def-item><term><italic>CYP2C9</italic></term><def><p>Cytochrome p450 family member 2c9</p></def></def-item><def-item><term><italic>GABRA1</italic></term><def><p>Gamma-aminobutyric acid-a receptor alpha1-subunit</p></def></def-item><def-item><term><italic>GABRA2</italic></term><def><p>Gamma-aminobutyric acid-a receptor alpha2-subunit</p></def></def-item><def-item><term><italic>GABRA3</italic></term><def><p>Gamma-aminobutyric acid-a receptor alpha3-subunit</p></def></def-item><def-item><term><italic>GAT3</italic></term><def><p>Gamma-aminobutyric acid transporter 3</p></def></def-item><def-item><term><italic>GSTM1</italic></term><def><p>Glutathione s-transferases mu 1</p></def></def-item><def-item><term>ILAE</term><def><p>International league against epilepsy</p></def></def-item><def-item><term><italic>MDR</italic>1</term><def><p>Multidrug resistance protein 1</p></def></def-item><def-item><term><italic>MDR2</italic></term><def><p>Multidrug resistance protein 2</p></def></def-item><def-item><term>ORs</term><def><p>Odds ratios</p></def></def-item><def-item><term>OXC</term><def><p>Oxcarbazepine</p></def></def-item><def-item><term><italic>P</italic></term><def><p><italic>P</italic>-value</p></def></def-item><def-item><term>P-gp</term><def><p>P-glycoprotein</p></def></def-item><def-item><term>PGt</term><def><p>Pharmacogenetics</p></def></def-item><def-item><term>PGx</term><def><p>Pharmacogenomics</p></def></def-item><def-item><term>PHT</term><def><p>Phenytoin</p></def></def-item><def-item><term>PRISMA</term><def><p>Preferred reporting items for systematic reviews and meta-analyses guidelines</p></def></def-item><def-item><term><italic>SCN1A</italic></term><def><p>Sodium channel nav1.1</p></def></def-item><def-item><term><italic>SCN2A</italic></term><def><p>Sodium channel nav1.2</p></def></def-item><def-item><term><italic>SLC6A4</italic></term><def><p>Solute ligand carrier family 6 member a4</p></def></def-item><def-item><term>SNP</term><def><p>Single nucleotide polymorphism</p></def></def-item><def-item><term>VPA</term><def><p>Valproic acid</p></def></def-item></def-list></glossary><ack><title>Acknowledgements</title><p>Not applicable.</p><sec id="FPar1"><title>Funding</title><p>Not applicable.</p></sec><sec id="FPar2"><title>Availability of data and materials</title><p>This study included articles which are available via PubMed. All information analysed in this study was collected in a dataset and this is available from the corresponding author on reasonable request.</p></sec><sec id="FPar3"><title>Authors’ contributions</title><p>M.C. and W.K. contributed equally to this work: designed the study, collected the data, conducted the analyses and wrote the manuscript. K.T. helped to perform the outcome analyses. H.K., I.B.Y.T. and L.H. revised the manuscript. 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