Gene Ther Mol Biol Vol 13, 152-157, 2009
Association analysis of the Tumor necrosis factor gene polymorphisms (TNFA 238 and 302) in the development of schizophrenia: Impact on the antipsychotic treatment response
Chi-Un Pae1,2*, Antonio Drago3, Alberto Chiesa3, Laura Mandelli3, Alessandro Serretti3, Tae-Youn Jun1
1Department of Psychiatry, The Catholic University of Korea College of Medicine, Bucheon, Kyounggi-Do, Republic of Korea
2Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
3Institute of Psychiatry, University of Bologna, Bologna, Italy
*Correspondence: Chi-Un Pae, MD, PhD, Department of Psychiatry, Holy Family Hospital, The Catholic University of Korea College of Medicine, 2 Sosa-Dong, Wonmi-Gu, Bucheon, Kyeonggi-Do 420-717, Republic of Korea; E-mail: firstname.lastname@example.org
Key Words: schizophrenia, tumor necrosis factor-α gene, and clinical variables.
Received: 25 May 2009; Revised: 2 June 2009;
Accepted: 4 June 2009; electronically published: 5 June 2009
This study investigated the tumor necrosis factor-α gene (TNFA; -238 G/A and -308 G/A polymorphisms) on the development of schizophrenia, as well as the interaction of the two polymorphisms in relation to symptomatology, family history, onset age and antipsychotic treatment response. Genomic DNA analyses with polymerase chain reaction (PCR) were used for the genotyping. One hundred and fifty-two (152) patients with schizophrenia and 152 normal controls participated in the study. Any associations between the individual polymorphism and schizophrenia were not found. However, marginal association between subjects with TNFA -238 A allele (genotype AA plus AG) and presence of family history was found (p=0.023). No significant interaction effects between TNFA –238 and -308 polymorphisms either on the development of schizophrenia or on clinical variables such as antipsychotics treatment response and psychopathology were found, although a significant interaction effect for subjects carrying TNFA -238 AG and -308 AA genotypes on a positive family history was observed (p=0.017). These results suggest that the interaction effects between TNFA –238 and -308 polymorphisms gives no significant contribution to the susceptibility to schizophrenia, and is not associated with clinical variables, antipsychotic treatment response and psychopathological features, except for family history of disease, at least in Korean population.
Various cytokines have been known to form the network between the immune system and the central nervous system. These cytokines show a change not only in the peripheral immune system but also in the central nervous system, and they exert their effects on the proliferation and death of immune cells; they are associated with neurotransmitters metabolism, neuronal development and degeneration (Muller and Ackenheil, 1998). TNF-α is a very important pro-inflammatory cytokine involved in the regulation of immune system and in the initial stage of inflammatory reaction, and it has been related to abnormal behaviors, anxiety, decreased appetite, emotions, sleep disturbances, recognition and other psychiatric symptoms highly expressed also in schizophrenia (Holden and Pakula, 1999;Kubota et al., 2001;Reichenberg et al., 2001;Strieter et al., 1993). In addition, the serum concentration of TNF-α in schizophrenic patients has been reported to be elevated in comparison with the control group. Moreover, after the administration of antipsychotic drugs, an alteration of its concentration has been detected, and thus its involvement not only in the development of schizophrenia but also in the response to treatment has been suggested (Erbagci et al., 2001;Monteleone et al., 1997;Naudin et al., 1997). TNF-α gene (TNFA) is located on chromosome 6p21.3 and was reported to be associated with schizophrenia (Schwab et al., 2000); the TNFA –238 (G/A) and –308 (G/A) polymorphisms are involved in the regulation of TNF-α activation, by influencing TNF-α transcription, thus being involved directly in the production of TNF-α (Kaluza et al., 2000;Wilson et al., 1994). According to the association of the TNFA polymorphism and schizophrenia, a correlation has been reported in literatures, with conflicting results (Boin et al., 2001;Czerski et al., 2008;Duan et al., 2004;Handoko et al., 2003;Hanninen et al., 2005;Hashimoto et al., 2004;Kampman et al., 2005;Meira-Lima et al., 2003;Morar et al., 2007;Pae et al., 2003;Riedel et al., 2002;Saviouk et al., 2005;Schwab et al., 2003;Shirts et al., 2006;Tan et al., 2003;Tsai et al., 2003;Watanabe et al., 2007;Zai et al., 2006), although a recent meta-analyses including 2512 cases and 3223 controls showed that the AA genotype was weakly associated with schizophrenia susceptibility in Caucasoids (Odd Ratio OR=1.65, 95% CI=1.00-2.71 Z=1.98 p=0.05) (Sacchetti et al., 2007).
To our knowledge, however, investigations about the association between TNF-α polymorphism and antipsychotic treatment response have been still inadequate to date. The aim of this study is to investigate the presence of an interaction effect of the TNF-α –308 and -238 polymorphisms on the development of schizophrenia and on the clinical symptomatology. Firstly we investigated the association between individual polymorphisms and the vulnerability to schizophrenia and to diverse clinical variables. Then, we compared and analyzed the influence of the interaction effects of the two polymorphisms on the affection status and various clinical variables.
One hundred and fifty-two (152) inpatients with schizophrenia and the 152 healthy controls participated in this study. The diagnosis was made on the basis of consensus between two board-certified psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) (American, 1994). The Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (SCID-I-CV) (First et al., 1997) was administered to all patients. Other available resources such as clinical course, family information and medical records were also used. Patients with a diagnosis of other mental or neurological disorders other than schizophrenia were excluded from the study. The control group consisted of volunteers from the paramedical- and medical-staffs or students who showed no family or personal history of major mental disorders and neurological diseases. The control group was also evaluated by board certified-psychiatrists to exclude current or a past history of psychiatric problems. A written informed-consent form was obtained from all subjects after a full description of the study. The Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1988) was assessed for examining the antipsychotics treatment response in patients with schizophrenia at the time of admission and 8 6weeks after antipsychotic administration (responder: defined as 20% decrease of PANSS score after 8-week treatment compared to that of PANSS score at the time of admission). Any antipsychotics regardless of class were given for the treatment of psychotic symptoms for 8 weeks. Risperidone (n=71) was the most frequently administered antipsychotic and then olanzapine (n=39), quetiapine (17), chlorpromazine (13) and haloperidol (12) were followed. One hundred and thirty-one (86.2%) patients completed the 8-week treatment. Thus, the 21 patientsÕ last data was obtained by a method of the last observation carried forward (LOCF).
B. Genotyping with Restriction Fragment Length Polymorphism (RFLP)
The DNA was extracted from whole blood using the standard method. Amplification of the target site of the TNF-α gene (TNFA –238, rs 361525 and –308, rs1800629) was carried out by PCR using forward (F) and reverse (R) primers (TNFA –238: F5'-ATC TGG AGG AAG CGG TAG TG-3' and R5'-AGA AGA CCC CCC TCG GAA CC-3'; TNFA –308: F5'-AGGCAATAGGTTTTGAGGGCCAT-3' and R5'-TCCTCCCTGCTCCGATTCCG-3') and conditions as described elsewhere (Wilson et al., 1994). The PCR products were digested at 37”C with NcoI (Boehringer Mannheim, Mannheim, Germany) to detect the TNFA –308 allele and with MspI (Boehringer Mannheim, Mannheim, Germany) to detect the TNFA –238 allele and then subjected to 8% acrylamide gel and stained with ethidium bromide. As for TNFA –238, Large 7(152bp) and small (132 bp/20 bp) fragments were identified as MspI site negative (TNFA –238 A allele) and positive (TNFA –238 G allele), respectively. As for TNFA –308, Large (107bp) and small (87 bp/20 bp) fragments were identified as NcoΙ site negative (TNFA –308 A allele) and positive (TNFA –308 G allele), respectively.
C. Statistical Analyses
Differences in the allele and genotype frequencies of the TNFA-238 and -308 polymorphisms between the patients and the controls were calculated using a Chi-square test. Hardy-Weinberg equilibrium at each polymorphism was examined by a goodness-of-fit Chi-square. To compare numerical variable such as age and the number of admission, nonparametric t-test, Univariate Analysis of Variance (ANOVA) and ANCOVA were used where appropriate. The Monte Carlo method with the CLUMP program v 1.9 (10,000 simulations) (Sham and Curtis, 1995) was used when small cell count observed in case of categorical comparison. Multiple regression analysis was applied to detect the possible interaction effects between the TNFA –238 and -308 polymorphisms in their influences on the affection status and other clinical variables (Serretti et al., 1999). The Linkage Disequilibrium (LD) was tested using a two-locus LD calculator (2 LD) (Zhao, 2004). The haplotypes were constructed using the EH program (Xie and Ott, 1993). P values <0.05 were considered significant. All the statistical tests were performed using the SPSS v10.0 software (SPSS Inc., Chicago, IL). The power of a sample to detect the differences between the alleles was calculated by considering an alpha value of 0.05, two tailed. Using these parameters, the sample was estimated to have the power (0.80) to detect a small to medium effect size (w=0.16), which corresponded to a difference of approximately 15% between the two groups in the two alleles.
Seventy-three (48.0%) patients with schizophrenia were male and 69 (45.4%) normal controls were male. No difference was present in the gender distribution between the two groups (p=0.730). The average age was older in the patient group (mean ± SD, 36.9±11.6 years) than in the control group (32.0±10.7 years) (p < 0.05).
The frequencies of TNFA -238 and -308 genotypes were not different from the expected values of Hardy-Weinberg equilibrium in the patients group (p=0.170 and p=0.883, respectively) and in the control group (p=0.112 and p=0.091, respectively, Table 1). Neither TNFA -238 nor TNFA -308 polymorphism variants were associated with the development of schizophrenia (Table 1).
The description of the patientsÕ characteristics with schizophrenia according to polymorphisms of TNFA -238 and TNFA -308 is shown in Tables 2 and 3. Subjects carrying TNFA -238 A allele had more frequent familial history [genotype AA and AG, p=0.023, odds ratio (OR)=5.156, 95% confidence intervals (CI)=1.463-18.107] (Table 2). Neither TNFA –238 polymorphism nor TNFA -308 variants were associated with the antipsychotic treatment response as a categorical variable (Tables 2 and 3).
Other clinical variables such as onset age, suicide history, past admission number and duration of illness were not associated with the two polymorphisms. When analyzing with the multiple regression approach all possible interactions between all the possible combinations of the two polymorphisms, significant interaction effects were not found with the development of schizophrenia as well as with several clinical variables such as family history, attempted suicide history, age at onset, duration of illness and antipsychotic treatment response. However, interaction effect between TNFA -238 AG genotype and –308 AA genotype was found to be associated with family history (beta=-0.432, p=0.017).
The D′ coefficient for the TNFA -238 and -308 polymorphisms was not indicative of significant LD (D′ =0.564) so that the haplotype analysis was not presented.
Table 1: The distribution of genotypeand allele in patients with schizophrenia and the controls
Table 2: Clinical parameters in patients with
schizophrenia according to TNFA -238 polymorphism
Table 3: Clinical parameters in patients with
schizophrenia according to TNFA -308 polymorphism
As for the association of TNFA polymorphism with schizophrenia, there have been mixed results, some studies supported (mainly with TNFA –308 polymorphism) (Czerski et al., 2008;Meira-Lima et al., 2003;Sacchetti et al., 2007;Saviouk et al., 2005;Schwab et al., 2000;Tan et al., 2003), while others failed to replicate the association of TNFA polymorphism with schizophrenia (Duan et al., 2004;Handoko et al., 2003;Hashimoto et al., 2004;Pae et al., 2003;Riedel et al., 2002;Shirts et al., 2006;Tsai et al., 2003;Watanabe et al., 2007;Zai et al., 2006). Since Boin et al. (Boin et al., 2001) found that TNFA –308 A allele was highly associated with a susceptibility to schizophrenia, which were replicated in other studies with different ethnicities (Caucasian and Brazilian and only one for Chinese) (Meira-Lima et al., 2003;Schwab et al., 2000;Tan et al., 2003).
Among the positive studies, interestingly, some found the positive association with TNFA -308 A allele with the susceptibility to schizophrenia, while others reported the positive association with TNFA -308 G allele, suggesting a complicated role of TNFA –308 polymorphism for schizophrenia. Furthermore, a pooled analysis with 2,399 patients with schizophrenia and 3,261 controls found that the TNFA –308 polymorphism was not associated with the development of schizophrenia, same result was given when the sample was stratified into different ethnics by the geographical origin though (i.e, Asian vs. Caucasian), which implicate the ethnic heterogeneity of the polymorphism (Duan et al., 2004).
Taken former studies together, our present findings regarding the TNFA –238 and -308 polymorphisms would be in the line with the majorities that did not prove the association of the TNFA -238 and -308 polymorphisms with schizophrenia (Boin et al., 2001;Duan et al., 2004;Handoko et al., 2003;Hanninen et al., 2005;Hashimoto et al., 2004;Meira-Lima et al., 2003;Pae et al., 2003;Riedel et al., 2002;Schwab et al., 2003;Tan et al., 2003;Tsai et al., 2003). Considering the lower frequency of A alleles in the two polymorphisms, we may need to collect larger samples and to conduct family-based studies. It should be also noted that the LD between TNFA –238 and -308 polymorphisms were not found in the present study, which is in line with the previous study (Duan et al., 2004), indicating less information of haplotype construction of the two polymorphisms for the development of schizophrenia until now, although available information on the LD on the TNFA polymorphisms would enhance the knowledge about the possible causative genes (Duan et al., 2004;Handoko et al., 2003;Tan et al., 2003). We found the subjects carrying TNFA -238 A allele (genotype AA or AG) were associated with positive familial history, suggesting this polymorphism would be an indicator for familial tendency of schizophrenia. However, the sub-analyses were performed with very small samples so that we need to be cautious in the interpretation of this finding. There have been little studies in relation to TNFA polymorphisms and antipsychotic treatment response. Recent study (Tsai et al., 2003) reported that TNFA –308 polymorphism might not be associated with clozapine response. Our study also failed to find any significant association of the two polymorphisms and antipsychotic response. This may suggest the TNFA -238 and -308 polymorphisms would not be associated with the improvement of psychopathology, although, we need more pharmacogenetic data with TNFA polymorphisms. In fact a recent study showed a marginal association of TNFA with antipsychotic response (Zai et al., 2006), indicating a need of more data in this area.
We tried to find possible interactions effects, unfortunately, we failed to find significant interactions except for positive association of the TNFA -238 AG and –308 AA with positive family history. As previously stated, the subjects with TNFA -238 allele A (genotype AA and AG) were associated with positive familial history, which may indicate the strong effect of TNFA –238 polymorphism on the familial aggregation for the development of schizophrenia considering the result of interaction and individual effects. Other interaction effects of the two polymorphisms on the other clinical variables were not found to be associated in patients with schizophrenia. The interaction between the two polymorphisms may not play a major role in development of schizophrenia and major clinical manifestations, or has only weak genetic influence. Different ethnic background for the two polymorphisms should be considered (Boin et al., 2001;Duan et al., 2004;Handoko et al., 2003;Meira-Lima et al., 2003;Pae et al., 2003;Tsai et al., 2003). Case-control association study has inherent pitfall of population stratification. More SNPs from the two genes should provide more accurate information. The multiple comparison issue should also be noted because the two polymorphisms were compared with regard to the genotype frequency and the allele distribution as well as the correlation with clinical variables including numerical and categorical parameters. We should consider the small sample number considering conventional sample size needed in the case-control association study (Sham and Curtis, 1995) which is related to the possibility of false negative finding with regard to sample size. Finally this study has only investigated the possibility of immunogenetical perspective in relation to pathophysiologies of schizophrenia but not tried to find other pathophysiological aspects such as neurotransmitters or neuroendocrine factors. Although, interaction effects may also partly reveal the potential role of specific genes for certain multi-factorial disorders, epistatic interaction among candidate genes for certain mental disorders might have us more chance to understand their genetic backgrounds and molecular underpinnings than simple interaction study.
In conclusion, the present study suggest that the interaction effects between TNFA -238 and -308 polymorphisms gives no significant contribution to the susceptibility to schizophrenia, and are not associated with clinical variables such as antipsychotic treatment response, except for family history, at least in Korean population. Consecutive studies with larger sample would be needed to draw any confirmative conclusion.
This study was supported by a grant of the Korean Health 21 R & D Project, Ministry of Health and Welfare, Republic of Korea (03-PJ10-PG13-GD01-0002 or A030001) and a support from the Medical Research Center, Korea Science and Engineering Foundation, Republic of Korea (R13-2002-005-04001-0).
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