Association Between EPHX1 Polymorphisms and Carbamazepine Metabolism in Epilepsy: a Meta‑Analysis

International Journal of Clinical Pharmacy (2019) 41:1414–1428 https://doi.org/10.1007/s11096-019-00919-y

REVIEW ARTICLE

Association between EPHX1 polymorphisms and carbamazepine metabolism in epilepsy: a meta‑analysis

Gui‑Xin Zhao1,2 · Ming‑Li Shen1,3 · Zheng Zhang4 · Ping Wang1,2 · Chun‑Xiang Xie1 · Gong‑Hao He1

Received: 17 April 2019 / Accepted: 9 October 2019 / Published online: 24 October 2019 © Springer Nature Switzerland AG 2019

Abstract Background EPHX1 gene polymorphisms were recently acknowledged as an important source of individual variability in carbamazepine metabolism, but the result of that association still remains controversial. Aim of the review To obtain a more precise estimation of the associations between EPHX1 polymorphisms and carbamazepine metabolism and resistance. Meth- ods The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched for appropriate studies regarding the rs1051740 and rs2234922 polymorphisms of EPHX1 up to September 2019. The meta-analysis was carried out using the Review Manager 5.3 software. The mean diference and 95% confdence interval were applied to assess the strength of the relationship. Results A total of 7 studies involving 1118 related epilepsy patients were included. EPHX1 rs1051740 polymorphism was signifcantly associated with adjusted concentrations of both carbamazepine (CC vs. TT: P = 0.02; CC vs. CT + TT: P = 0.005) and carbamazepine-10,11-epoxide (CC vs. CT + TT: P = 0.03). Furthermore, EPHX1 rs2234922 polymorphism was also observed to be signifcantly associated with decreased adjusted concentrations of carbamazepine- 10,11-trans dihydrodiol (GG vs. GA + AA: P = 0.04) and CBZD:CBZE ratio (GG vs. AA: P = 0.008; GG vs. GA + AA: P = 0.0008). Nevertheless, the pooled analysis showed that the EPHX1 polymorphisms had no signifcant efect on CBZ resistance. Conclusion EPHX1 rs1051740 and rs2234922 polymorphisms may afect the carbamazepine metabolism; but carbamazepine resistance was not related to any of the single nucleotide polymorphisms investigated. These fndings provided further evidence for individualized therapy of epilepsy patients in clinics.

Keywords Carbamazepine · EPHX1 · Epilepsy · Meta-analysis · Metabolism · Polymorphism

Impacts on Practice

• The CC genotype of rs1011740 is associated with a Gui-Xin Zhao, Ming-Li Shen and Zheng Zhang contributed reduction in serum concentrations of carbamazepine equally to this work. when compared to the TT and CT + TT genotypes. • The GG genotype of rs2234922 decreases serum concen- Electronic supplementary material The online version of this trations of carbamazepine-10,11-trans dihydrodiol in the article (https://doi.org/10.1007/s11096-019-00919-y) contains supplementary material, which is available to authorized users. recessive model and reduces CBZD:CBZE ratio in the additive and recessive models. * Gong‑Hao He • The fndings of this meta analysis help to improve indi- [email protected] vidualized therapy of epilepsy patients in clinics. 1 Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, 212 Daguan Rd., Kunming 650032, China 2 Kunming Medical University, Kunming 650500, China 3 Dali University, Dali 671000, China 4 Medical Engineering Section, The 306th Hospital of PLA, Beijing 100101, China

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Background recommended to optimize its dose [2]. The causes for the interindividual variability of daily maintenance doses of CBZ vary Carbamazepine (CBZ), a dibenzazepines antiepileptic drug, is from environmental factors, co-medication to genetic variation prescribed worldwide as a frst-line treatment for focal or gen- [3, 4], among which genetic variation of drug-metabolizing eralized tonic–clonic epileptic seizures [1]. It is considered as enzymes has been widely concerned recently and was sug- an essential medicine by the World Health Organization. How- gested to have a major impact on drug therapy for epilepsy ever, CBZ has a relatively narrow therapeutic range (4–12 μg/ [5, 6]. mL) and a therapeutic drug monitoring of CBZ was therefore

Fig. 1 Flow diagram for process of included studies selection

1 3 1416 International Journal of Clinical Pharmacy (2019) 41:1414–1428 [ 23 ] [ 21 ] [ 26 ] [ 24 ] [ 30 ] [ 25 ] [ 22 ] Ref - rs1051740 rs2234922 rs1051740 rs1051740 rs2234922 rs1051740 rs2234922 rs1051740 rs2234922 rs1051740 rs2234922 rs1051740 rs2234922 Polymor phism PB PB PB PB PB PB PB DNA DNA source RFLP - Sequenc ing and Man Taq - Sequenc ing and PCR– RFLP RFLP - Sequenc ing and PCR– RFLP and PCR– RFLP PCR– Direct Direct Taq Man Taq Direct Direct PCR– Direct Direct Taq Man Taq Genotyping Genotyping methods 5 8 8 5 5 5 8 NOS NOS Score Case–con - Case–con - Case–con - Case–con - Case–con - Case–con - Case–con - trol trol trol trol trol trol trol Study Study design 63.3 ± 7.6 68.3 ± 16 43.3 ± 16.8 64.96 ± 11.31 49.22 ± 16.6 63.29 ± 7.65 60.12 ± 10.51 Weight/kg Weight/kg (mean ± SD) 19 ± 15.09 32.9 ± 15.5 36.2 ± 16.5 11.2 ± 3.5 38.26 ± 17 34.75 ± 15.83 39.23 ± 11.88 Age/years Age/years (mean ± SD) 118(52/66) 166(91/75) 145(82/63) 210(119/91) 83(53/30) 162(104/58) 234(111/123) Number Number (male/female) 28.16 months Over 1 year Over Over 1 year Over Over 1 year Over Over 1 year Over Over 1 year Over Over 1 year Over Treatment Treatment duration 8.51 ± 3.21 10.04 ± 3.14 8.18 ± 3.91 10.93 ± 5.00 7.28 ± 2.73 NO NO Dose/mg/kg/ ± SD) day(mean CBZ CBZ CBZ CBZ CBZ CBZ CBZ Drug Epilepsy Epilepsy Epilepsy Epilepsy Epilepsy Epilepsy Epilepsy Subjects China Tunisia China Kosovo China China China Taiwan, Taiwan, - Popula tion 2016 2015 2015 2014 2013 2012 2012 Year Characteristics included in this meta-analysis of all studies PCR-restriction fragment length fragment polymorphism, PB Peripheral deviation blood, SD Standard scale, CBZ Carbamazepine, PCR–RFLP PCR-restriction Newcastle–Ottawa CC Chbili C Ma CL Daci A Zhu X Yun W Yun Ru JL Ru Hung 1 Table First author NOS

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◂Fig. 2 Forest plot for association between EPHX1 rs1051740 poly- Infrastructure (CNKI), Chinese Science and Technique Jour- morphism and CBZ metabolism in additive model (a). Sensitivity nals Database (VIP), China Biology Medicine disc (CBM) analysis for efect of EPHX1 rs1051740 polymorphism on CDR , CBZ and Wan fang Data. Information site using the following CDRCBZE and CBZE:CBZ ratio in additive model (b) terms: “carbamazepine”, “EPHX1” or “microsomal epoxide hydrolase” and “polymorphism” or “genotype”. The search CBZ is catalyzed by cytochrome P450 3A4 (CYP3A4) strategies for PubMed were provided as a sample in sup- to produce active metabolite carbamazepine-10,11-epoxide plementary materials. We searched for trials without lan- (CBZE), which possesses a potent anticonvulsant efect [7, guage and year of publication restrictions and references of 8]. Subsequently, CBZE is hydrolysed via microsomal epoxide retrieved articles were also searched and reviewed to fnd hydrolase (mEH), which is encoded by the EPHX1 gene, to additional eligible studies. The last search was updated in an inactive metabolite carbamazepine-10,11-trans dihydrodiol September 2019. When multiple publications on the same (CBZD) [7, 9, 10]. It was previously reported that the obvious study population were identifed, only the most recent or individual variability in drug pharmacokinetics and pharmaco- complete study was used in this meta-analysis. The literature dynamics of CBZ was mainly ascribed to the genetic variation retrieval was performed by two independent authors. of EPHX1 [11-14]. Therefore, the genetic polymorphisms in EPHX1 may be an important source of interindividual vari- Inclusion and exclusion criteria ability in CBZ metabolism. Human EPHX1 gene spans 35.48 kb and is located on Studies fulflling the following criteria were considered as chromosome 1 (1q42.12) [15-17]. Among the validated eligible for inclusion in this meta-analysis: (a) case–control single nucleotide polymorphisms (SNPs) in EPHX1 gene, studies (b) evaluation of the associations between the geno- two SNPs (i.e., rs1051740 and rs2234922) were intensively types of EPHX1 rs1051740 and rs2234922 polymorphisms investigated [18-20]. However, studies investigating the asso- and plasma concentration or resistance of CBZ in epilepsy ciations between EPHX1 gene polymorphisms and enzyme (c) each patient was administrated with CBZ monotherapy activities exhibited inconsistent fndings. For example, it was and not receiving pharmacological treatment for other shown that patients carrying the CC genotype of rs1051740 pathologies (d) no liver or renal diseases were reported (e) were associated with a lower plasma concentration of CBZ including at least three studies for each polymorphism to as compared with the CT or TT genotype, suggesting a high allow calculation of publication bias between studies, and metabolism in patients with the CC genotype [21, 22]. On the (f) studies based on any ethnicity population were eligible. contrary, several other studies indicated that rs1051740 had no Exclusion criteria were the following: (a) insufcient infor- signifcant infuence on plasma concentration of CBZ [23-25]. mation for data extraction (b) reviews and case reports (c) Additionally, similar inconsistent results were also observed not human research, and (d) outcomes not in our focus of for carriers of rs2234922 polymorphism. It was reported that interest. the CBZD:CBZE ratio was signifcantly lower in rs2234922 GG carriers than in GA or AA carriers [23] although these Data extraction fndings were not confrmed in other studies [24, 26, 27]. Information was carefully extracted from all eligible publications by two independent authors, including author’s name, Aim of the review publication date, country, sample size, plasma concentration and adjusted serum concentration of CBZ (CDR CBZ), Based on this background, in order to achieve a more rational CBZE (CDRCBZE) and CBZD (CDRCBZD), CBZE:CBZ and and individualized use of CBZ in clinical treatment, we hereby CBZD:CBZE ratios, genotypes distribution, drug resistant conducted a systematic meta-analysis to evaluate the associa- patients (defned as no change or less than 50% reduction in tions of EPHX1 rs1051740 and rs2234922 polymorphisms seizure frequency for at least 1 year during treatment with with CBZ metabolism and resistance, trying to provide nec- CBZ) and drug responsive patients (defned as seizure-free essary power to assess the efect of EPHX1 genetic variations. or a 50% or greater reduction in seizure frequency for at least 1 year during treatment with CBZ) [26, 28]. If diverse results were generated, the disagreement was resolved by discussion Methods between the two authors or by asking a third investigator. The authors of the studies were contacted for additional data Search strategy when necessary and applicable.

Relevant papers were searched through PubMed, EMBASE, Cochrane library, Chinese National Knowledge

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◂Fig. 3 Forest plot for association between EPHX1 rs1051740 poly- according to the guidelines of the International League morphism and CBZ metabolism in recessive model (a). Sensitivity Against Epilepsy [31]. All the patients were treated with analysis for efect of EPHX1 rs1051740 polymorphism on CDR , CBZ CBZ in a dose range of 400–1200 mg/day. The source of CDRCBZE and CBZE:CBZ ratio in recessive model (b) DNA was peripheral venous blood, and the genetic polymorphisms were assayed either by PCR–RFLP, Tap Man Assessment of methodological quality Assay or direct DNA sequencing. The NOS scores of the included studies ranged from 5 to 8 based on the NOS evalu- We used the Newcastle–Ottawa scale (NOS) for assessing ation system, indicating a relatively high quality of included the quality of the included studies in this meta-analysis [29]. studies. Furthermore, a test of funnel plot was not conducted Using this scale system, each included study was judged on due to the insufcient number of studies in the present study. three broad perspectives: the selection of the study groups, the comparability of the groups, and the ascertainment of Associations between EPHX1 rs1051740 outcome of interest. High-quality studies were identifed polymorphism and CBZ metabolism with a NOS score of fve or more, whereas those with less than a score of fve were considered as low-quality studies. Additive model (CC vs. TT)

Statistical analysis Seven studies evaluated the association between rs1051740 polymorphism and CBZ metabolism. Outcomes, such as We conducted the review using the Review Manager 5.3 the adjusted concentrations of CBZ, CBZE and CBZD, software. Comparisons of the dichotomous variables were were reported in 7, 3 and 3 articles, respectively; while the performed using odds ratio (OR) with 95% confidence metabolic ratios (i.e., CBZE:CBZ and CBZD:CBZE) data interval (CI). For continuous variables, the standard mean were evaluated in 3 articles. In the additive model, the CC diferences (Std. MD) with 95% CI were used. Z-test was genotype signifcantly decreased CDR CBZ compared with TT 2 performed to determine the statistical signifcance of results genotype (P = 0.02, I Het = 81%). But no signifcant associa- 2 with statistical signifcance defned as P < 0.05. Heteroge- tions were observed in the CDR CBZE (P = 0.05, I Het = 99%), 2 neity between articles was assessed by Cochrane’s Q-test. CDRCBZD (P = 0.35, I Het = 6%), CBZE:CBZ ratio (P = 1.00, 2 2 2 Data with low heterogeneity (P ≥ 0.10 and I ≤ 50%) were I Het = 78%) or CBZD:CBZE ratio (P = 0.55, I Het = 0%) analyzed by a fxed-efects model while a random-efect (Fig. 2a). The sensitivity analysis was performed by exclud- model was used for data with high heterogeneity. To explore ing each study successively, which efectively abrogated sources of heterogeneity, the leave-one-out sensitivity analy- the heterogeneity and did not infuence the present results sis was also conducted. Furthermore, a funnel plot was used (Fig. 2b). to evaluate the publication bias when applicable. Recessive model (CC vs. CT + TT)

Results Similar to the CC versus TT data, the CC genotype also decreased CDR CBZ as compared with CT + TT genotype 2 Study selection and qualitative assessment (P = 0.005, I Het = 70%), but did not significantly affect 2 the CDR CBZD (P = 0.65, I Het = 23%), CBZE:CBZ ratio 2 As shown in Fig. 1, the initial search strategy identifed 118 (P = 0.83, I Het = 77%) or CBZD:CBZE ratio (P = 0.40, 2 studies in the electronic databases, from which 42 were I Het = 0%) (Fig. 3a). The leave-one out sensitivity analysis excluded for duplication. Then, we excluded 69 studies decreased heterogeneity and did not afect the overall results after a careful full-text review of the remaining 76 studies, (Fig. 3b). Moreover, the CC genotype was initially found to which included 33 irrelevant studies, 17 review articles or increase CDRCBZE but with substantial between-study het- 2 commentaries, 5 in vitro or animal studies, 14 studies with erogeneity (P = 0.03, I Het = 99%) (Fig. 3a). However, when insufcient data. Eventually, 7 studies [21-26, 30] including the study by Chbili et al. [23] was removed in sensitivity 1118 participants were included according to the present analysis, the association became insignifcant with the het- 2 inclusion and exclusion criteria. erogeneity relatively reduced (P = 0.97, I Het = 74%), indicat- The characteristics of included studies are presented ing instability of this outcome (Fig. 3b). in Table 1. These studies were published between 2012 and 2016 from diferent countries. All participants in the Other models studies were epilepsy patients and were treated with CBZ monotherapy at a stable maintenance dose. The classifca- As for the rest genetic models, our meta-analysis did not tion of epilepsies and epileptic syndromes were conducted observe any associations between rs1051740 polymorphism

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Fig. 4 Forest plot for association between EPHX1 rs2234922 polymorphism and CBZ metabolism in additive model

and the metabolism of CBZ in heterozygous model (CT vs. Associations between EPHX1 rs2234922 TT), dominant model (CC + CT vs. TT) and co-dominant polymorphism and CBZ metabolism model (CT vs. CC + TT) (supplemental Fig. S1a, Fig. S2a and Fig. S3). The sensitivity analysis was also conducted Additive model (GG vs. AA) by excluding each study successively, which abrogated the heterogeneity but did not infuence the present results (sup- Six studies assessed the association between EPHX1 plemental Fig. S1b and Fig S2b). rs2234922 polymorphism and CBZ metabolism. The adjusted concentrations of CBZ, CBZE and CBZD were reported in 6, 3 and 3 articles, respectively. There were 2 articles that measured CBZE:CBZ ratio, while CBZD:CBZE ratio was evaluated in 3 articles. For additive model, the results showed that the GG genotype reduced CBZD:CBZE ratio compared with the wild-type homozygote AA geno- 2 type (P = 0.008, I Het = 21%), and no statistically signifcant

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Fig. 5 Forest plot for association between EPHX1 rs2234922 polymorphism and CBZ metabolism in recessive model heterogeneity was observed (Fig. 4). As for other outcomes, was not conducted because this outcome was only involved we did not fnd any association in this model (Fig. 4). Sig- in 2 studies. nifcant heterogeneity was found regarding the CBZE:CBZ ratio. However, the sensitivity analysis was not performed Other models because of the limited number of included studies regarding this outcome. Our meta-analysis found no associations in heterozygous model (GA vs. AA), dominant model (GG + GA vs. AA) Recessive model (GG vs. GA + AA) and co-dominant model (GA vs. GG + AA) (supplemental Fig. S4a, Fig. S5a and Fig. S6a). Sensitivity analysis abro- When compared with the GA + AA genotypes, the GG gated the heterogeneity but did not alter the initial results 2 genotype decreased CDRCBZD (P = 0.04, I Het = 0%) and of CDR CBZ, CDR CBZE and CDR CBZD (supplemental Fig. 2 CBZD:CBZE ratio (P = 0.0008, I Het = 0%) (Fig. 5). No S4b, Fig. S5b and Fig. S6b). However, for CBZD:CBZE associations were observed in the CDR CBZ (P = 0.33, ratio, sensitivity analysis changed the association result. 2 2 I Het = 46%), CDRCBZE (P = 0.09, I Het = 0%), or CBZE:CBZ After excluding one study [26], signifcant main efects (for 2 ratio (P = 0.38, I Het = 98%) (Fig. 5). The sensitivity analysis CBZD:CBZE ratio) were observed in heterozygous model

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Fig. 6 Sensitivity analysis for efect of EPHX1 rs2234922 polymorphism on CBZD:CBZE ratio in heterozygous model (a), dominant model (b) and co-dominant mode (c)

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Fig. 7 Forest plot for association between EPHX1 rs1051740 polymorphism and CBZ resistance in additive model, heterozygous model, recessive model, dominant model and co-dominant model

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Fig. 8 Forest plot for association between EPHX1 rs2234922 polymorphism and CBZ resistance in additive model, heterozygous model, recessive model, dominant model and co-dominant model

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2 (P = 0.03, I Het = 0%) (Fig. 6a), dominant mode (P = 0.002, CDRCBZE compared with CT + TT genotype. These might 2 I Het = 0%) (Fig. 6b) and co-dominant model (P = 0.04, be owing to the possibility that the CC genotype impedes 2 I Het = 0%) (Fig. 6c). mEH enzymatic activity according to previous reports [37, 38]. Overall, our results suggested that the rs1051740 poly- Associations between EPHX1 rs1051740 morphism may afect CBZ plasma levels and therapeutic and rs2234922 polymorphisms and CBZ resistance efcacy of CBZ although further original studies based on high-quality are still needed. There were 4 studies that evaluated the roles of EPHX1 With regard to rs2234922, it is located in the exon 4 of rs1051740 and rs2234922 polymorphisms in CBZ resist- EPHX1 and characterized by substitution of arginine for his- ance, respectively. For rs1051740, the overall OR with its tamine at the position 139 (A416G, His139Arg) [17]. It was 95% CI did not show any associations between this polymor- previously indicated that this kind of amino acid substitution phism and CBZ resistance in all models, and no statistically afected the afnity of mEH to its substrate and resulted in signifcant heterogeneity was observed (Fig. 7). With regard enzyme activity change [18]. Our present results observed to the rs2234922, we also did not fnd any associations in all that this SNP decreased CDRCBZD in the recessive model genetic models (Fig. 8). and reduced CBZD:CBZE ratio in additive and recessive models, which further confrmed that rs2234922 decreased enzymatic activity of mEH and were consistent with previ- Discussion ous fundamental research fndings [13]. However, it should be noted that this SNP was also reported to increase mEH activity according to earlier in vitro studies [18, 20]. This Epilepsy is the most common chronic neurological disease diferential efect of rs2234922 on mEH activity may be characterized by recurrent seizures [32]. The therapeu- ascribed to the facts either that the protein stabilities of Arg tic goal is to maximize seizure control while minimizing substitution in the transfected cells were diferent from those adverse drug efects, thus improving quality of life [33]. in human tissues [13, 39] or that this SNP infuenced enzyme CBZ is one of the most commonly used anticonvulsants in activity in a substrate-specifc way [15]. In this regard, addi- the treatment of epilepsy [3]. However, its slow absorption tional studies are warranted to clarify these issues and vali- and wide inter-individual variability in oral administration date the present meta-analysis results. may lead to variation in its therapeutic efcacy [34, 35]. As for the data instability of CDR (for rs1051740) Genetic variants are known to infuence the individual daily CBZE and CBZD:CBZE ratio (for rs2234922) according to the maintenance doses for epilepsy in addition to infuencing a leave-one-out sensitivity analysis, the reason might be that patient’s response to therapy [10, 36]. Therefore, elucidating the total sample sizes of the 2 outcomes were relatively lim- the role of genetic polymorphisms on pharmacokinetics and ited, which led to downgrading the quality of the evidence. pharmacodynamics of CBZ would contribute to efective Therefore, these results should be interpreted cautiously and individualized therapy of epilepsy patients in clinics. well-designed studies are necessary. To our knowledge, this study for the frst time reviewed It was noteworthy that, on one hand, one previous study the existing literatures and explored the associations between demonstrated that rs1051740 CC and CT genotypes were EPHX1 polymorphisms and CBZ metabolisms by meta- signifcantly associated with CBZ resistance in Thai patients analysis. Our results provided comprehensive evidence to with epilepsy [40]. Regretfully, this article could not be suggest that the rs1051740 and rs2234922 polymorphisms included in the present work because of data insufciency. were associated with metabolisms of CBZ, which refected On the other hand, no associations were found based on the the potential efect of EPHX1 gene on clinical treatment present 4 included studies conducted in Chinese, Kosovar, of epilepsy. Furthermore, the outcomes of included studies and Tunisian epilepsy patients, respectively [23, 25, 26, were reported completely and the quality score represented 30], which was also inconsistent with the results of CBZ a reliable quality of evidence, indicating relatively fne com- metabolism. This might be due to the diferent geographi- pleteness of proof in our present meta-analysis. cal distributions of subjects, age or environmental factors The rs1051740 within exon 3 of EPHX1 is characterized [4, 41]. However, the included studies did not provide any by substitution of histidine for tyrosine at the amino acid information regarding these confounding factors for further position 113 (site T337C, amino acid change Tyr113His) evaluation. In addition, the number of studies that evalu- [17]. In this meta-analysis, the rs1051740 polymorphism ated the roles of EPHX1 rs1051740 and rs2234922 poly- was found to be associated with decreased CDR , indicat- CBZ morphisms in CBZ resistance is also limited, which might ing that this SNP had certain efect on the serum CBZ con- mask their actual connection as a result. Consequently, fur- centration in epilepsy patients. Furthermore, we found that ther investigations based on more well-designed experiments patients with the rs1051740 CC genotype exhibited higher

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