Genetic association analysis of the glutathione peroxidase (GPX1) gene polymorphism (Pro197Leu) with tardive dyskinesia

Psychiatry Research 141 (2006) 123 – 128 www.elsevier.com/locate/psychres

Genetic association analysis of the glutathione peroxidase (GPX1) gene polymorphism (Pro197Leu) with tardive dyskinesia Takahiro Shinkai a,b,*, Daniel J. Mu¨ller a,e, Vincenzo De Luca a, Sajid Shaikh a, Chima Matsumoto b, Rudi Hwang a, Nicole King a, Joseph Trakalo a, Natalia Potapova a, Gwyneth Zai a, Hiroko Hori b, Osamu Ohmori b,d, Herbert Y. Meltzer c, Jun Nakamura b, James L. Kennedy a a

Neurogenetics Section, Centre for Addiction and Mental Health, Clarke Division, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada, M5T 1R8 b Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan c Department of Psychiatry, Division of Psychopharmacology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA d Wakato Hospital, Wakamatsu-ku, Kitakyushu, 808-0132, Japan e Department of Psychiatry, Charite´ University Medicine Berlin, Campus Charite´ Mitte, D-10117 Berlin, Germany Received 15 March 2004; accepted 8 June 2004

Abstract A possible involvement of oxidative stress in the pathophysiology of tardive dyskinesia (TD) has previously been proposed (reviewed in [Andreassen, O.A., Jorgensen, H.A., 2000. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Progress in Neurobiology 61, 525–541.]). Long-term administration of neuroleptics alters dopaminergic turnover, which results in increased formation of reactive oxygen species (ROS). This is hypothesized to lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a possible functional polymorphism of the human glutathione peroxidase (GPX1) gene (an important antioxidant enzyme) was studied in 68 chronic treatment–refractory patients with schizophrenia. A proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) in the GPX1 gene was genotyped. No significant difference in total Abnormal Involuntary Movements Scale (AIMS) scores was observed among patients in the three genotype groups. Moreover, no significant differences in genotype or allele frequencies were observed between subjects with and without TD. Our results suggest that the GPX1 gene polymorphism does not confer increased susceptibility to TD, although further studies are warranted before a conclusion can be drawn. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Tardive dyskinesia; Schizophrenia; Glutathione peroxidase; Oxidative stress; Free radical; Polymorphism; Genetics

* Corresponding author. Department of Psychiatry, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu City, 807-8555, Japan. Tel.: +81 93 691 7253; fax: +81 93 692 4894. E-mail address: [email protected] (T. Shinkai). 0165-1781/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2004.06.023

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1. Introduction Tardive dyskinesia (TD) is an involuntary movement disorder that affects around 20% of cases treated chronically with antipsychotics as a serious adverse effect (Morgenstern and Glazer, 1993). Several mechanisms for the pathophysiology of TD have been hypothesized including dopamine receptor supersensitivity (Tarsy and Baldessarini, 1977), involvement of serotonergic (5-HT) system (Meltzer, 1994), and gamma amino-butyric acid (GABA) insufficiency (Casey et al., 1980). Nevertheless, the pathophysiology of TD is inadequately understood. TD is considered a complex side effect of long-term antipsychotic treatment (Jeste and Kelsoe, 1997). Recently, positive associations between TD and several genetic polymorphisms have been reported (reviewed in Ohmori et al., 2003 and Mu¨ller et al., 2004), including dopamine D3 receptor (Steen et al., 1997; Basile et al., 1999; Lerer et al., 2002), cytochrome P450 (CYP) 2D6 (Kapitany et al., 1998; Ohmori et al., 1998), 1A2 (Basile et al., 2000), 5HT2A receptor (Segman et al., 2001), and 5-HT2C receptor (Segman et al., 2000) genes. These data provide some support for the genetic predisposition to TD and imply the availability of individualized medicine for TD in the future, which would be based on pharmacogenetics in the treatment and prevention of TD taking interindividual difference of the patients’ genetic profiles into account. Several lines of evidence suggest that oxidative stress may play a role in the pathogenetic mechanism in TD (reviewed in Andreassen and Jorgensen, 2000). Long-term administration of antipsychotics alters dopaminergic neurotransmissions by increasing the turnover of dopamine (DA) (See, 1991) and the dopamine receptors in the basal ganglia (Bischot et al., 1993). An important route for metabolism of dopamine is via monoamine oxidase (MAO) yielding dopamine quinones and hydrogen peroxide (H2O2), which in turn leads to the formation of reactive oxygen species (ROS). ROS cause neuronal damage as a consequence of oxidative stress. Several studies have shown that chronic typical antipsychotics (e.g., haroperidol or chlorpromazine) but not atypical antipsychotics (e.g., clozapine) significantly induced lipid peroxidation, a major index of oxidative stress, and decreased antioxidant enzymes in rat brains (Naidu et al., 2002). It is

also worth noting that quercetin, a potent antioxidant, reduced haloperidol-induced vacuous chewing movements (VCMs) dose-dependently (Naidu et al., 2003). Further support comes from findings that increased lipid peroxidation products have been found in the cerebrospinal fluid (CSF) of patients with TD (Lohr et al., 1990; Tsai et al., 1998). In addition, vitamin E, a free radical scavenger, has been proposed as a treatment to prevent or decrease the severity of TD and several studies have shown the effect of vitamin E on TD symptoms (reviewed in Butterfield et al., 2002). Based on the oxidative stress hypothesis of TD, we have reported a positive association between a functional polymorphism (Ala 9Val) in the gene of manganese superoxide dismutase (MnSOD), an important antioxidant enzyme, in a Japanese sample of schizophrenia (Hori et al., 2000). In that study, we found decreased 9Ala allele in patients with TD compared to patient without TD ( P = 0.02; OR 0.29; 95% CI 0.10–0.83), suggesting that the 9Ala allele might play a protective role against TD. Zhang et al. (2002) have failed to replicate our findings. They, however, found a significant positive correlation between total AIMS score and MnSOD activity, which implies a general role of oxidative stress-related genes in pathogenesis of TD. The human glutathione peroxidase (GPX1; MIM# 138320) is a selenium-dependent enzyme which plays an important role in the detoxification of free radicals (Yao et al., 2001). GPX1 knockout mice show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide (de Haan et al., 1998). The GPX1 protein is ubiquitously expressed in the human body including the brain, and is found in cytoplasm and mitochondria (Ursini et al., 1985). The human GPX1 gene has been located on chromosome 3p21.3 (Kiss et al., 1997), and it is composed of two exons within a 1.42 Kb region (Ishida et al., 1987). A single nucleotide polymorphism (SNP) in the GPX1 gene has been reported at nucleotide 593, C to T substitution which causes a proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) (Forsberg et al., 1999). The effect of the Pro197Leu polymorphism on the function of GPX1 enzyme is considerable. Although one study reported that erythrocyte GPX1 activity showed no significant difference between the genotypes (Forsberg et al., 2000), a more recent study using

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human transfected cells, which exclusively express either the Pro- or Leu-containing GPX1 allele, showed functional differences between the two alleles (Hu and Diamond, 2003). In that study, Hu and Diamond demonstrated that the Leu-containing allele was less responsive to the stimulation of GPX1 enzyme activity. Based on the oxidative stress hypothesis of TD, in the present study, we studied the association between TD and the Pro197Leu polymorphism in the GPX1 gene in patients with schizophrenia.

2. Materials and methods 2.1. Clinical sample Our sample included 68 unrelated patients (52 men and 16 women) with DSM-IIIR diagnoses of schizophrenia recruited from Case Western Reserve University by HYM. Patients were either treatment-refractory or intolerant to typical antipsychotic therapy (Kane et al., 1988). Written informed consent was obtained from each patient included in this study. Patients were an average of 31.8 (F 9.3) years old with ages ranging from 16 to 58. The sample was 73.5% Caucasian and 26.5% African American. Ethnicity was determined from the place of birth of the patient, their parents and grandparents, as well as mother tongue and religion. This information came from a standardized form filled out by the clinician for each patient. Patients had been treated with typical antipsychotics from at least 2 chemical classes for a minimum of one year. As well, in the 5 years leading up to inclusion in the study, patients had all received at least 3 periods of treatment in which doses equivalent or greater than 1000 mg/day of chlorpromazine were given for at least 6 weeks. Each treatment period failed to result in a significant relief of symptoms (Kane et al., 1988). None of these patients had previously been treated with atypical neuroleptics. A washout period of 2–4 weeks was utilized before TD was assessed. The washout period was a requirement of a separate study of treatment response (Masellis et al., 1998), but also had the advantage of allowing patients to fully express their TD phenotype. TD is often masked and is represented in various subtypes of TD as described in Schooler and Kane (1982). Following the washout period patients were assessed for TD severity using the Abnormal Involuntary Movement

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Scale (AIMS) (Guy, 1976). TD assessment was carried out by HYM, a clinician who has extensive experience in TD severity. A diagnosis of TD according to Schooler–Kane criteria (1982) was also performed using the AIMS scores. 2.2. Genetic analysis Three 10 ml EDTA tubes of blood were drawn from patients and their parents, and genomic DNA was extracted using the high salt method of Lahiri and Nurnberger (1991). Genotypes were assessed by the TaqMan allele specific assay method (Applied Biosystems, Foster City, CA) according to the manufacturer’s protocols. The Pro197Leu polymorphism site was amplified by polymerase chain reaction (PCR) using the following primers: 5V-CATCGAAGCCCTGCTGTCT-3V (forward) and 5V-CACTGCAACTGCCAAGCA-3V (reverse). Two dual labeled probes centered on the SNP and differing in sequence by the 1-bp polymorphism of the SNP site itself were designed by Applied Biosystems Inc. The probes were labeled with 5V reporter fluors VIC or 6-FAM and 3V quencher. The probe sequences were: VIC-ACAGCTGGGCCCTT and 6-FAM-ACAGCTGAGCCCTT. PCR amplifications were performed on an ABI PRISMR 7000 Sequence Detection System (Applied Biosystems) with the reaction mixture in a total volume of 25 Al, consisting of 40 ng of genomic DNA, 2 TaqMan Universal Master Mix (Applied Biosystems), 40 Assay-By-Design SNP Genotyping Assay Mix (Applied Biosystems), which includes the primers and labeled probes above, and deionized H2O. After denaturing at 95 8C for 10 min, 45 cycles of PCR were performed under the following conditions: 92 8C for 15 s and 60 8C for 1 min. All genotypes were reported with the allelic discrimination program using the ABI software and confirmed by two experienced researchers. Samples which gave ambiguous calls were genotyped again. 2.3. Statistical analysis The fitness of genotype frequency distribution to the Hardy–Weinberg equilibrium was calculated by the v 2 goodness-of-fit test. Differences in the demographic characteristics and total AIMS scores were assessed among subjects with the three Pro197Leu genotypes

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Table 1 Demographic characteristics and the total AIMS score according to the GPX1 Pro197Leu genotype Genotype Pro/Pro Gender (F/M) Age (years, mean F S.D.) Ethnicity (Caucasian/ African American) Total AIMS score (mean F S.D.)

P Pro/Leu

Leu/Leu

10/29 6/21 0/2 0.69a 31.4 F 9.4 32.0 F 9.38 34.5 F 12.0 0.93b 29/10

19/8

2/0

0.65a

6.2 F 8.9

3.1 F 4.9

2.0 F 2.8

0.24b

Monte Carlo test: gender (v 2 = 0.74, d.f. = 2), ethnicity (v 2 = 0.87, d.f. = 2). b Kruskal–Wallis test: age (v 2 = 1.44, d.f. = 2), total AIMS score (v 2 = 2.89, d.f. = 2).

distributions in patients with TD (v 2 = 0.62, d.f. = 1, P = 0.43) and in patients without TD (v 2 = 0.89, d.f. = 1, P = 0.35) were within the Hardy–Weinberg equilibrium. No significant difference in genotype frequencies was detected between subjects with and without TD (v 2 = 2.30, d.f. = 2, P = 0.32). In addition, there was no significant difference with respect to the allele frequencies (v 2 = 1.96, d.f. = 1, P = 0.16).

4. Discussion

a

using the Kruskal–Wallis test (age and total AIMS score) and the Monte Carlo test (gender and ethnicity) (Table 1). Differences in the demographic characteristics between subjects with and without TD were assessed using the v 2 test (gender, age, and allele), the Mann–Whitney U-test (age), and the Monte Carlo test (genotype) (Table 2). Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, Chicago, IL), version 10.0. In addition, the Monte Carlo methods were used to evaluate the contingency table with small cell counts using CLUMP, a computer program (Sham and Curtis, 1995).

In the present study, we employed two approaches in evaluating the association between the Pro197Leu polymorphism in the GPX1 gene and TD. First, we assessed differences in the total AIMS scores among the three Pro197Leu genotype groups, with the results showing no significant differences in the total AIMS scores. Second, we assessed differences in genotype and allele frequencies between patients with and without TD, with the results also showing no significant differences in these frequencies. These results provided no evidence of an association between the Pro197Leu polymorphism and TD. From the power calculation regarding our sample using SPSS Sample Power software for Windows, we estimated that our sample has a power of 77% to detect a medium effect size (w = 0.25) and of 19% to detect a

3. Results

Table 2 Demographic characteristics and the GPX1 Pro197Leu genotype based on analysis of a dichotomous trait (with and without TD)

Demographic characteristics and genotype distributions are shown in Table 1. The distribution was within the Hardy–Weinberg equilibrium (v 2 = 1.12, d.f. = 1, P = 0.29). The allele frequency of 197Leu was 0.23. There were no significant differences in gender, age, or ethnicity among subjects with the tree genotypes. The total AIMS scores (mean F S.D.) in subjects with the three genotypes were 6.18 F 8.89 (Pro/ Pro), 3.07 F 4.86 (Pro/Leu), and 2.00 F 2.83 (Leu/ Leu). There were no significant differences among the three genotype groups ( P = 0.24). Results of the analysis of a dichotomous trait in relation to TD diagnosis are shown in Table 2. There were significant differences in age ( P = 0.021) between subjects with and without TD. The genotype

Gender (F/M) Age (years, mean F S.D.) Ethnicity (Caucasian/ African American) Genotypec Pro/Pro Pro/Leu Leu/Leu Allelec Pro Leu a

2

2

With TD (N = 20)

Without TD (N = 48)

P

6/14 36.6 F 10.8

10/38 29.8 F 7. 9

0.42a 0.021b

14/6

36/12

0.67a

14 (0.70) 6 (0.30) 0 (0.00)

25 (0.52) 21 (0.44) 2 (0.04)

0.32d

34 (0.85) 6 (0.15)

71 (0.74) 25 (0.26)

0.16a 2

v test: gender (v = 0.66, d.f. = 1), ethnicity (v = 0.18, d.f. = 1), allele (v 2 = 1.96, d.f. = 1). b Mann–Whitney U-test. c Genotype and allele counts are shown with frequencies in parenthesis.

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small effect size (w = 0.10) at the P b 0.05 level for allele comparison using the v 2 test between subjects with and without TD. Accordingly, the likelihood that we have committed a type II error with our sample size cannot be excluded, especially with the association between the polymorphism and TD being quite weak. The present study does have limitations besides the sample size. First, we assessed abnormal involuntary movements by a single cross-sectional examination and a second assessment of TD was not made in the present study. A second assessment to establish the diagnosis of persistent TD (Schooler and Kane, 1982) would increase the power of the results by removing false positives. Second, the assessment of other movement disorders such as parkinsonism or withdrawalemergent dyskinesias were not methodically made in the present study. The presence of other movement disorders may mask dyskinetic movement. Third, there were significant differences in age between subjects with and without TD in our analysis of the dichotomous trait of TD diagnosis, presenting limitations to analyzing differences in allele and genotype frequencies between patients with and without TD. Nevertheless, it may be natural that the mean age of subjects with TD is higher than that of those without TD, as Latimer (1995) suggests that age is more consistently identified as a risk factor for TD than are such other risk factors as current neuroleptic dose and female gender. In addition, the study of Miller et al. (1995) has shown that only age, but not gender and daily neuroleptic dose, had a significant influence on the development of TD in chronic psychiatric patients. Fourth, although genotypic distribution did not vary between Caucasians and African-Americans, the inclusion of two different ethnicities may have lead to unnoticed stratification effects. Finally, the use of a case-control study design is also a limitation of this study as this methodology is vulnerable to the effect of population stratification. Taking these limitations of the present study into account, further studies, preferably using larger and ethnically homogeneous samples, are warranted before a conclusion can be drawn.

Acknowledgements This work was supported by grant #MOP15007 from the Canadian Institutes of Health Research

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