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Glutathione S-transferase M1 polymorphism may contribute to schizophrenia in the Korean population

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Glutathione S-transferase M1 polymorphism may contribute to schizophrenia in the Korean population
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  Original article 147 Glutathione S-transferase M1 polymorphism may contributeto schizophrenia in the Korean population Chi-Un Pae a , Hye-Sook Yu a , Jung-Jin Kim a , Won Kim b , Chang-Uk Lee a ,Soo-Jung Lee a , Tae-Youn Jun b , Chul Lee a , In-Ho Paik  a andAlessandro Serretti c The association between Glutathione S-Transferase M1gene (GSTM1) polymorphism and schizophrenia wasexamined. One hundred and eleven in-patients withschizophrenia and 130 healthy controls were enrolled inthis study. Genotyping was performed using a polymerasechain reaction-based method. The GSTM1 null genotypewas significantly more frequent in the schizophreniapatients than in the controls ( P  =0.014, odds ratio=1.93,95% confidence interval=1.115–3.351). On the other hand,the GSTM1 genotype variants were not associated withtardive dyskinesia or total abnormal involuntary movementscale scores.This study suggests that, at least in the Korean population,the GSTM1 polymorphism may confer susceptibility tothe development of schizophrenia but not to tardivedyskinesia.  Psychiatr Genet   14:147–150  c  2004 LippincottWilliams & Wilkins. Psychiatric Genetics  2004,  14: 147–150 Keywords: schizophrenia, glutathione S-transferase M1 gene (GSTM1)polymorphism a Department of Psychiatry, Kangnam St Mary’s Hospital, The Catholic Universityof Korea College of Medicine, Banpo-Dong, Seocho-Gu, Seoul, Korea, b Department of Psychiatry, St. Mary’s Hospital, The Catholic University of KoreaCollege of Medicine, Yoido-Dong, Youngdeungpo-Gu, Seoul, Korea and c Department of Psychiatry, Vita-Salute University, San Raffaele Institute, Milan,Italy.Sponsorship: This study was supported by Grant Number M6-0225-00-0001from the Korean Institute of S&T Evaluation and Planning (KISTEP).Correspondence and requests for reprints to In-Ho Paik, Department ofPsychiatry, Kangnam St Mary’s Hospital,The Catholic University of Korea Collegeof Medicine, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Korea.Tel: +82 2 590 1532; fax: +82 2 536 8744; e-mail: knpsy@catholic.ac.kr Received  6 June 2003  Revised  29 July 2003 Accepted  22 September 2003 Introduction  An impaired antioxidant defense system has beensuggested to be a liability factor in the development of schizophrenia. A recent study  (Akyol  et al. , 2002) foundthat oxidative stress and the antioxidant activities inschizophrenic patients are altered compared with normalcontrols, indicating a possible role of increased oxidativestress and diminished enzymatic antioxidants in thepathophysiology of schizophrenia (Mahadik   et al. , 2001).Similar findings have been reported: reduced plasmaantioxidants such as albumin and bilirubin (Yao  et al. ,2000, Pae  et al. , 2004), reduced essential polyunsaturatedfatty acids (Khan  et al. , 2002), reduced plasma uric acidlevels (Yao  et al. , 1998b), and a reduced status of theplasma total antioxidant capacity  (Yao  et al. , 1998a). Inline with these findings, catecholamines can oxidizeeither spontaneously or enzymatically, to form quinonesincluding the highly neurotoxic semiquinones that arefree radicals (Smythies, 1999). Dopamine is also oxidizedto toxic free radical dopamine semiquinones by a reactivenitrogen species under an impaired antioxidant system(Smythies, 1999). This may lead to a membrane dysfunc-tion, the neuronal degeneration of the dopaminergicneurons in the specific brain regions such as themesolimbic area and inflammatory response in the brain,which have been implicated in schizophrenia (Smythies,1999). Furthermore, the failure of this antioxidant systemhas been linked to the free radical-mediated pathology,clinical symptomatology, the side effects of the antipsy-chotics including tardive dyskinesia (TD), and the noveltreatment strategies in schizophrenia (Yao  et al. , 2001).Glutathione s-Transferase M1 (GSTM1) is an interestingantioxidant enzyme that is involved in the detoxificationof cathecholamine  o -quinones and also prevents theformation of reactive oxygen species by interrupting theredox cycle between aminochrome and semiquinones(Smythies, 1997; Harada  et al. , 2001b). Therefore, it ispossible that a GSTM1 defect could partially account forthe pathogenesis of schizophrenia in terms of theinfluence of the disturbed activity of GSTM1 on thedetoxification process of neurotoxic semiquinones, re-sulting in an excess of neurotoxic quinones in the brain(Harada  et al. , 2001b). In line with these findings,Harada  et al.  (2001b) reported that the GSTM1 nullgenotype is associated with an increased susceptibility toschizophrenia. In their study, the frequency of theGSTM1 null genotype in schizophrenia patients was65.5% and 49.4% in the controls. Overall, it will beimportant whether these findings could be correlatedwith the adrenochrome hypothesis of schizophrenia(Smythies, 2002). 0955-8829  c 2004 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.  Therefore, a replication study of the association for theGSTM1 gene polymorphism between the patients withschizophrenia and controls was performed, and therelationship between the clinical variables such as theonset age, TD and the GSTM1 polymorphism wasfurther analyzed in the schizophrenia patients. Materials and methods One hundred and eleven inpatients with schizophreniaand 130 voluntary controls participated in this study.Diagnosis was made by consensus between two board-certified psychiatrists (C.-U.P. and C.-U.L.) according tothe DSM-IV criteria of schizophrenia (American Psychia-tric Association, 1994). The Structured Clinical Interviewfor DSM-IV Axis I Disorders – Clinician Version (First  et al. , 1997) was assigned to all the patients. Subjects withneurological illnesses and medico-surgical illnesses wereexcluded from this study. Among the patients, TD wasdetermined using a single cross-sectional measurement of the abnormal involuntary movement scale (AIMS) (Guy,1976) according to the probable TD criteria of Schooler–Kane (Schooler and Kane, 1982), by the one of theauthors (C.-U.P.). The antipsychotics administered to thepatients were haloperidol, chlorpromazine, and trifluo-perazine.The voluntary controls were recruited from hospitalpersonnel and visitors to the public health center inKangnam St Mary’s Hospital. Prior to collecting the bloodsamples, a direct interview was used to determinewhether the subjects had a current psychiatric problemor a history of psychiatric illness. Both the patients andcontrols were composed of native Korean descendantswho were biologically unrelated. The nature of the study was conveyed to all subjects and written informedconsent was obtained. The Ethics Committee of theKangnam St Mary’s Hospital approved this study.The DNA was extracted from whole blood using thestandard method, and the GSTM1 genotyping wasperformed by a polymerase chain reaction under modifiedconditions according to a previously reported method(Brockmoller  et al. , 1992). Briefly, the genotyping wascarried out in a Perkin Elmer 9600 thermocycler (FosterCity, California, USA) using forward and reverse GSTM1primers (5 0 -CGC CAT CTT GTG CTA CAT TGC CCG-3 0 and 5 0 -TTC TGG ATT GTA GCA GAT CA-3 0 ,respectively), with the  b -globin gene (primers, 5 0 -CAA CTT CAT CCA CGT TCA CC-3 0 and 5 0 -GAA GAG CCA  AGG ACA GGT AC-3 0 ) as an internal control to confirmthe amplification reaction. Thirty microliters of thereaction mixture consisted of the following: 50mmol/lKCl, 10mmol/l Tris–HCI (pH 8.3), 1.5mmol/l MgCl 2 ;0.25mmol/l each primer, 20 m mol/l dNTPs, 100nggenomic DNA and 1 U Taq DNA polymerase (BoehringerMannheim, Mannheim, Germany). After an initialdenaturation step at 94 1 C for 5min, the samples wereprocessed through 35 cycles of 94 1 C for 45s, 55 1 C for45s, and 72 1 C for 1min. A final extension at 72 1 C for5min was then performed. The samples were run in a 2%agarose gel electrophoresis with ethidium bromidestaining and visualized under UV light.Comparisons of the GSTM1 genotype distribution in thisstudy were examined by a Fisher’s Exact test. Continuousvariables were analyzed by an independent  t   test betweenthe comparison groups where appropriate. An analysis of covariance with the duration of the antipsychotic treat-ment as a covariate was run for a comparison of the AIMSscores across the two GSTM1 genotypic groups.  P  <0.05was considered significant. All the statistical tests wereperformed using SPSS version 10.0 software (SPSS Inc.,Chicago, Illinois, USA). Results  A total 39.6% of the patients with schizophrenia (  n =111)were male, and 43.1% of the controls (  n =130) weremale. The gender and age distribution in the two groupswas not significantly different ( P  =0.589 and  P  =0.393).The age distribution in the two genotypic groups was notsignificantly different ( P  =0.829).The genotype distributions in the patients ( P  =0.56) andthe controls ( P  =0.97) were in Hardy–Weinberg equili-brium. The GSTM1 null genotype in the schizophreniapatients was significantly higher than that of the controls,as presented in Table 1. The odds ratio was 1.93 with a95% confidence interval of 1.115–3.351, suggesting anincreased risk of developing schizophrenia. However, thedistribution of the GSTM1 genotypes according to theage of onset ( r 25 years versus >25 years) was notsignificantly different (data not shown,  P  =0.842). Thetotal AIMS score revealed no significant differencesacross the two GSTM1 genotypic groups (2.2±2.7 and2.4±2.7, respectively;  P  =0.787). As for patients groupwith or without TD, the distribution of the GSTM1genotypes was not significantly different in the twogroups (Table 1). The patients with TD were generally older than the patients without TD. Discussion The GSTM1 gene is anchored on chromosome 1p13.3(Gilliland  et al. , 2002), where it is close to a region thathas been linked to the susceptibility to schizophrenia(Shaw  et al. , 1998; Garver  et al. , 2001) and a polymorphismof the GSTM1 gene is caused by a complete deletion of the gene, which leads to the loss of enzymatic function.The presence of the GSTM1 null genotype reduces thephase II function of detoxification that is related to DNA damage and an excess of neurotoxic compounds (Brock-moller  et al. , 1992; Harada  et al. , 2001a). The functionalsignificance of the polymorphism is that subjects with a 148  Psychiatric Genetics  2004, Vol 14 No 3 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.  heterozygote as well as a homozygote have biologicalsignificance on the GSTM1 activity, indicating that aheterozygote can overcome the deficiency and maintainthe enzyme activity, although more data on this point willbe needed (McLellan  et al. , 1997; Gronau  et al. , 2003).Similar to a previous study  (Harada  et al. , 2001b), thepresent study found that the GSTM1 null genotype inpatients with schizophrenia was significantly higher thanthat of the controls. However, the distribution of theGSTM1 genotypes according to the onset age ( r 25 years versus >25 years) was not different. This study could not find an association between the total AIMSscore and the GSTM1 genotypes, as well as thedistribution of GSTM1 genotypes between the patientswith or without TD. These findings suggest that aGSTM1 polymorphism may be involved in the suscept-ibility to schizophrenia itself but not as a modifying factornor as a side effect for the disorder. However, theunidentified surrounding genes, which are in linkagedisequilibrium with the GSTM1 polymorphism, shouldnot be discounted. In addition, other candidates for theschizophrenia in terms of genetic contribution tooxidative stress and antioxidant system should beconsidered. Finally, it is possible that the suppression of antipsychotic medications on TD in a special subgroup,those who appeared to be free of TD, may weaken thepower to detect an association of TD.Ethnic differences in the GSTM1 polymorphism havebeen reported. African-Americans showed a lower fre-quency (25.6%) of the GSTM1 null genotype comparedwith Asians (47.9%) and Caucasians (non-Hispanic,45.3%; Hispanic, 40.9%) (Gilliland  et al. , 2002). This isin line with our findings as well as with the results of studies conducted in the Japanese population (Harada  et al. , 2001a, 2001b). These differences will requirefurther investigation with a different ethnic background.The power analysis showed that the sample size in thisstudy had the power (0.80) to detect a small to mediumallele association ( w =0.18), which is similar to that( w =0.17) reported by Harada  et al.  (2001b). Finally, anassociation study can result in spurious associationsbetween a phenotype and unlinked candidate loci,indicating the need for further studies based on thefamily data or of unlinked genetic markers to detectpopulation stratification (Pritchard and Rosenberg, 1999).The controls in this study could not be representative of the general Koreans.In conclusion, this study found that the GSTM1polymorphism might be involved in the susceptibility toschizophrenia in the Korean population. Further investi-gations aimed at accumulating data on the role of aGSTM1 polymorphism in the pathogenesis of schizo-phrenia should be conducted. References Akyol O, Herken H, Uz E, Fadillioglu E, Unal S, Sogut S,  et al.  (2002). The indicesof endogenous oxidative and antioxidative processes in plasma fromschizophrenic patients. The possible role of oxidant/antioxidant imbalance. Prog Neuropsychopharmacol Biol Psychiatry   26 :995–1005.American Psychiatric Association (1994).  Diagnostic and Statistical Manual of Mental Disorders , 4th edition (DSM-IV). Washington, DC: AmericanPsychiatric Association.Brockmoller J, Gross D, Kerb R, Drakoulis N, Roots I (1992). Correlation betweentrans-stilbene oxide-glutathione conjugation activity and the deletion mutationin the glutathione S-transferase class mu gene detected by polymerase chainreaction.  Biochem Pharmacol   43 :647–650.First MB, Spitzer RL, Gibbon M, Williams JBW (1997).  Structured Clinical Interview for DSM-IV—Clinician Version (SCID-CV) . Washington, DC:American Psychiatric Press.Garver DL, Holcomb J, Mapua FM, Wilson R, Barnes B (2001). Schizophreniaspectrum disorders: an autosomal-wide scan in multiplex pedigrees. Schizophr Res  52 :145–160.Gilliland FD, Gauderman WJ, Vora H, Rappaport E, Dubeau L (2002). Effects ofglutathione-S-transferase M1,T1, and P1 on childhood lung function growth. Am J Respir Crit Care Med   166 :710–716. Table 1  Characteristic of the demographics and glutathione S-transferase M1 gene polymorphism in patients with schizophrenia and thecontrols Patients ( n =111) Controls ( n =130)With TD ( n =49) Without TD ( n =62) TotalSex a (male/female) 19/30 25/37 44/67 56/74Age b (years) 48.8±8.4 45.2±8.7 46.8±8.7 45.9±7.4Duration of illness c (years) 20.8±10.2 18.8±9.9 19.7±10.0Current antipsychotic dose d 945.9±124.1 904.0±133.2 922.5±130.3Duration of antipsychotic treat-ment (years) e 18.9±9.9 16.2±9.6 17.4±9.8Genotype f,g Null 30 (61.2) 40 (64.5) 70 (63.1) 61 (46.9)Present 19 (38.8) 22 (35.5) 41 (36.9) 69 (53.1)Data presented as mean±standard deviation or number (%). With tardive dyskinesia (TD) versus without TD. a w 2 =0.027, degrees of freedom (d.f.)=1,  P  =0.87; b P  =0.03; c P  =0.29; d chlorpromazine equivalent dose (mg/day),  P  =0.09; e P  =0.91; f w 2 =0.763, d.f.=1,  P  =0.382. g Total versus control,  w 2 =6.287, d.f.=1,  P  =0.014. GSTM1 polymorphism and schizophrenia  Pae  et al.  149 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.  Gronau S, Koenig-Greger D, Jerg M, Riechelmann H (2003). GSTM1 enzymeconcentration and enzyme activity in correlation to the genotype ofdetoxification enzymes in squamous cell carcinoma of the oral cavity.  Oral Dis  9 :62–67.Guy W (1976). Abnormal involuntary movement scale (AIMS). In:  ECDEU Assessment Manual for Psychopharmacology  ,  Revised  . Washington, DC:Department of Health, Education and Welfare, US DHEW publication;pp. 534–537.Harada S, Fujii C, Hayashi A, Ohkoshi N (2001a). An association betweenidiopathic Parkinson’s disease and polymorphisms of phase II detoxificationenzymes: glutathione S-transferase M1 and quinone oxidoreductase 1 and 2. Biochem Biophys Res Commun  288 :887–892.Harada S, Tachikawa H, Kawanishi Y (2001b). Glutathione S-transferase M1gene deletion may be associated with susceptibility to certain forms ofschizophrenia.  Biochem Biophys Res Commun  281 :267–271.Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, Mahadik SP (2002).Reduced erythrocyte membrane essential fatty acids and increased lipidperoxides in schizophrenia at the never-medicated first-episode of psychosisand after years of treatment with antipsychotics.  Schizophr Res  58 :1–10.Mahadik SP, Evans D, Lal H (2001). Oxidative stress and role of antioxidant andomega-3 essential fatty acid supplementation in schizophrenia.  ProgNeuropsychopharmacol Biol Psychiatry   25 :463–493.McLellan RA, Oscarson M, Alexandrie AK, Seidegard J, Evans DA, Rannug A,Ingelman-Sundberg M (1997). Characterization of a human glutathione S-transferase mu cluster containing a duplicated GSTM1 gene that causesultrarapid enzyme activity.  Mol Pharmacol   52 :958–965.Pae CU, Paik IH, Lee C, Lee SJ, Kim JJ, Lee CU (2004). Decreased plasmaantioxidants in schizophrenia.  Neuropsychobiology   50 :54–56.Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J,  et al.  (1998).A genome-wide search for schizophrenia susceptibility genes.  Am J Med Genet   81 :364–376.Schooler NR, Kane JM (1982). Research diagnoses for tardive dyskinesia.  ArchGen Psychiatry   39 :486–487.Smythies JR (1997). Oxidative reactions and schizophrenia: a review discussion. Schizophr Res  24 :357–364.Smythies J (1999). Redox mechanisms at the glutamate synapse and theirsignificance: a review.  Eur J Pharmacol   370 :1–7.Smythies J (2002). The adrenochrome hypothesis of schizophrenia revisited. Neurotoxicity Res  4 :147–150.Pritchard JK, Rosenberg NA (1999). Use of unlinked genetic markers to detectpopulation stratification in association studies.  Am J Hum Genet   65 :220–228.Yao JK, Reddy R, van Kammen DP (1998b). Reduced level of plasma antioxidanturic acid in schizophrenia.  Psychiatry Res  80 :29–39.Yao JK, Reddy R, McElhinny LG, van Kammen DP (1998a). Reduced status ofplasma total antioxidant capacity in schizophrenia.  Schizophr Res 32 :1–8.Yao JK, Reddy R, van Kammen DP (2000). Abnormal age-related changes ofplasma antioxidant proteins in schizophrenia.  Psychiatry Res  97 :137–151.Yao JK, Reddy RD, van Kammen DP (2001). Oxidative damage andschizophrenia: an overview of the evidence and its therapeutic implications. CNS Drugs  15 :287–310. 150  Psychiatric Genetics  2004, Vol 14 No 3 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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