Psychiatry Research 226 (2015) 521–522
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Meta-analysis of associations between tumor necrosis factor-α polymorphisms and schizophrenia susceptibility To the Editors: Schizophrenia is a mental disorder characterized by a breakdown of thought processes and poor emotional responsiveness. Although the etiology of schizophrenia is not fully understood, it has been suggested to involve interactions between a susceptible genetic background and environmental factors. Studies have shown increased levels of pro-inflammatory cytokines in the peripheral and central nervous system (CNS) of patients with schizophrenia, suggesting an association between immune dysfunction and schizophrenia (Kayser and Dalmau, 2011). Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine that plays an important role in inflammatory and immune responses, including those observed in schizophrenia (Rooney et al., 1995). The TNF gene is located on chromosome 6 within the class III region of HLA, and several single-nucleotide polymorphisms have been identified on its promoter (Allen, 1999). TNF-α 308 A/G (rs1800629), 238 A/G (rs361525), 857 T/C (rs1799724), 863 T/C (rs1800630), and 1031 C/T (rs1799964) are the most commonly studied polymorphisms in schizophrenia. In the present study, we explored whether the TNF-α 308 A/G, 238 A/G, 857 T/C, 863 T/C, and 1031 C/T polymorphisms are associated with susceptibility to schizophrenia using a metaanalysis approach. A literature search was conducted for studies that examined associations between TNF-α polymorphisms and schizophrenia. The MEDLINE and EMBASE citation indexes were used to identify articles, dated up to January 2014, in which the presence of TNF-α polymorphisms was determined in schizophrenia patients and controls. Studies were included in the analysis if they: (1) were case-control studies; (2) included patients with schizophrenia; and (3) included genotype data for the TNF-α polymorphisms. No language restriction was applied. We excluded the following: (1) studies containing overlapping data; (2) studies in which the genotypes could not be ascertained; (3) studies in which family members had been included and the analysis was based on linkage considerations; and (4) studies in which the genotype distribution in controls was not consistent with Hardy–Weinberg equilibrium (HWE), because deviation from HWE among controls suggests the possibility of biased control selection or genotyping errors. Meta-analyses were performed using: (1) allelic contrast; (2) homozygote contrast; (3) recessive models; and (4) dominant models. The point estimates of ORs and their 95% confidence intervals (CIs) were determined for each study. Cochran's Qstatistics were used to assess within- and between-study variations and heterogeneities (Higgins and Thompson, 2002). When a significant Q-statistic indicated heterogeneity across studies, the http://dx.doi.org/10.1016/j.psychres.2015.02.012 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
random effects model was used for the meta-analysis, and when heterogeneity across studies was not indicated, the fixed effect model was used. Fifteen relevant studies met the study inclusion criteria (Dai et al., 2008; Debnath et al., 2013; Duan et al., 2004; Hanninen et al., 2005; Hashimoto et al., 2004; Kampman et al., 2005; Naz et al., 2011; Pae et al., 2003; Riedel et al., 2002; Sacchetti et al., 2007; Shirts et al., 2006; Tsai et al., 2003; Watanabe et al., 2007; Zai et al., 2006; Zhong et al., 2011). One schizophrenia genome-wide association study (GWAS) showing no allelic association between TNF-α 308 A/G (rs1800629), TNF-α 1031 C/T (rs1799964) polymorphisms and schizophrenia (OR ¼0.993, p ¼0.966; OR ¼1.110, p ¼0.226) was not included in this meta-analysis because genotype data were not available (Stefansson et al., 2009). The meta-analysis showed no association between the TNF-α 308 A allele and schizophrenia when all subjects were considered (OR ¼ 1.103, 95% CI ¼0.910– 1.338, P ¼0.318). After stratification by ethnicity, meta-analysis indicated that the TNF-α 308 A allele was not associated with schizophrenia in European and East Asian populations. No association between schizophrenia and the TNF-α 238 A/G and –857 T/C polymorphisms was found by meta-analyses. However, meta-analysis indicated an association between the TNF-α 1031 CC þ CT genotype and schizophrenia in Asian population (OR ¼1.259, 95% CI ¼1.044–1.518, P ¼ 0.016) (Fig. 1). We evaluated publication bias by using Egger's linear regression test (Egger et al., 1997), which measures funnel plot asymmetry using a natural logarithm scale of ORs. Egger's regression test showed no evidence of publication bias in the meta-analysis of the TNF-α polymorphisms (Egger's regression test p-values 4 0.1). Previous studies have shown that the TNF-α 1031 C/T polymorphism might have functional significance (Kesarwani et al., 2009). TNF-α 1031 is a regulatory site for TNF-α transcription, and increased TNF-α gene transcription leads to TNF-α overproduction (Kesarwani et al., 2009). However, whether the association between the TNF-α 1031 C/T polymorphism and schizophrenia susceptibility is due to a causal association or a LD with the true diseasecausing polymorphism remains to be determined. In conclusion, this meta-analysis demonstrates no relationship between TNF-α 308 A/G, 238 A/G, 857 T/C, or 863 T/C polymorphisms and schizophrenia susceptibility, but the TNF-α 1031 C/T polymorphism is associated with the development of schizophrenia in Asians.
Conflict of interest The authors have no financial or non-financial conflict of interest to declare.
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Letter to the Editor / Psychiatry Research 226 (2015) 521–522
Fig. 1. Forrest plot for the association between the CC þ CT genotype of the TNF-α 1031 A/G polymorphism and schizophrenia in Asian population.
Acknowledgments This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References Allen, R.D., 1999. Polymorphism of the human TNF-alpha promoter – random variation or functional diversity? Molecular Immunology 36, 1017–1027. Dai, J., Ahan, ZH, Cai, GH, Huang, JW, 2008. Association analysis of tumor necrosis factor alpha promoter polymorphisms with schizophrenia. Chinese Journal of Behavioral Medical Science 17, 625–627. Debnath, M., Mitra, B., Bera, N.K., Chaudhuri, T.K., Zhang, Y.P., 2013. Lack of association of IL-6 ( 174G 4C) and TNF-alpha ( 238G 4A) variants with paranoid schizophrenia in Indian Bengalee population. Cytokine 61, 455–458. Duan, S., Xu, Y., Chen, W., Liu, Z., Guo, T., Gao, J., Bian, L., Zheng, Y., Li, X., Zhang, X., Pan, Y., Gu, N., Feng, G., He, L., 2004. No association between the promoter variants of tumor necrosis factor alpha (TNF-alpha) and schizophrenia in Chinese Han population. Neuroscience Letters 366, 139–143. Egger, M., Davey Smith, G., Schneider, M., Minder, C., 1997. Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629–634. Hanninen, K., Katila, H., Rontu, R., Mattila, K.M., Hurme, M., Lehtimaki, T., 2005. Tumor necrosis factor-alpha – G308A polymorphism in schizophrenia in a Finnish population. Neuroscience Letters 385, 76–81. Hashimoto, R., Yoshida, M., Ozaki, N., Yamanouchi, Y., Iwata, N., Suzuki, T., Kitajima, T., Tatsumi, M., Kamijima, K., Kunugi, H., 2004. Association analysis of the 308G4 A promoter polymorphism of the tumor necrosis factor alpha (TNFalpha) gene in Japanese patients with schizophrenia. Journal of Neural Transmission 111, 217–221. Higgins, J.P., Thompson, S.G., 2002. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 21, 1539–1558. Kampman, O., Anttila, S., Illi, A., Mattila, K.M., Rontu, R., Leinonen, E., Lehtimaki, T., 2005. Interaction of tumor necrosis alpha–G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 255, 279–283. Kayser, M.S., Dalmau, J., 2011. The emerging link between autoimmune disorders and neuropsychiatric disease. The Journal of Neuropsychiatry and Clinical Neurosciences 23, 90–97. Kesarwani, P., Mandhani, A., Mittal, R.D., 2009. Polymorphisms in tumor necrosis factor-A gene and prostate cancer risk in North Indian cohort. The Journal of Urology 182, 2938–2943. Naz, M., Riaz, M., Saleem, M., 2011. Potential role of Neuregulin 1 and TNF-alpha (-308) polymorphism in schizophrenia patients visiting hospitals in Lahore, Pakistan. Molecular Biology Reports 38, 4709–4714.
Pae, C.U., Chae, J.H., Bahk, W.M., Han, H., Jun, T.Y., Kim, K.S., Kwon, Y.S., Serretti, A., 2003. Tumor necrosis factor-alpha gene polymorphism at position -308 and schizophrenia in the Korean population. Psychiatry and Clinical Neurosciences 57, 399–403. Riedel, M., Kronig, H., Schwarz, M.J., Engel, R.R., Kuhn, K.U., Sikorski, C., Sokullu, S., Ackenheil, M., Moller, H.J., Muller, N., 2002. No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 252, 232–234. Rooney, M., David, J., Symons, J., Di Giovine, F., Varsani, H., Woo, P., 1995. Inflammatory cytokine responses in juvenile chronic arthritis. British Journal of Rheumatology 34, 454–460. Sacchetti, E., Bocchio-Chiavetto, L., Valsecchi, P., Scassellati, C., Pasqualetti, P., Bonvicini, C., Corsini, P., Rossi, G., Cesana, B.M., Barlati, S., Gennarelli, M., 2007. -G308A tumor necrosis factor alpha functional polymorphism and schizophrenia risk: meta-analysis plus association study. Brain, Behavior, and Immunity 21, 450–457. Shirts, B.H., Bamne, M., Kim, J.J., Talkowski, M., Wood, J., Yolken, R., Nimgaonkar, V.L., 2006. A comprehensive genetic association and functional study of TNF in schizophrenia risk. Schizophrenia Research 83, 7–13. Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietiläinen, O.P., Mors, O., Mortensen, P.B., 2009. Common variants conferring risk of schizophrenia. Nature 460, 744–747. Tsai, S.J., Hong, C.J., Yu, Y.W., Lin, C.H., Liu, L.L., 2003. No association of tumor necrosis factor alpha gene polymorphisms with schizophrenia or response to clozapine. Schizophrenia Research 65, 27–32. Watanabe, Y., Muratake, T., Kaneko, N., Fukui, N., Nara, Y., Someya, T., 2007. No association between the tumor necrosis factor-alpha gene promoter polymorphisms and schizophrenia in a Japanese population. Psychiatry Research 153, 1–6. Zai, G., Muller, D.J., Volavka, J., Czobor, P., Lieberman, J.A., Meltzer, H.Y., Kennedy, J.L., 2006. Family and case-control association study of the tumor necrosis factor-alpha (TNF-alpha) gene with schizophrenia and response to antipsychotic medication. Psychopharmacology 188, 171–182. Zhong, H.J., Peng, L., Zhu, Y.S., Dang, J., Huo, Z.H., 2011. Association of the polymorphisms in the promoter region of tumor necrosis factor alpha and interleukin 6 genes with schizophrenia. Zhonghua yi xue yi chuan xue za zhi ¼Zhonghua yixue yichuanxue zazhi ¼Chinese Journal of Medical Genetics 28, 427–431.
Young Ho Lee n, Gwan Gyu Song Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea E-mail address: [email protected] (Y.H. Lee) Received 30 December 2014 16 February 2015 20 February 2015 Available online 26 February 2015
n Correspondence to: Division of Rheumatology, Department of Internal Medicine, Korea University, Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea. Tel.: þ 82 2 920 5645; fax: þ 82 2 922 5974.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Meta-analysis of associations between tumor necrosis factor-α polymorphisms and schizophrenia susceptibility To the Editors: Schizophrenia is a mental disorder characterized by a breakdown of thought processes and poor emotional responsiveness. Although the etiology of schizophrenia is not fully understood, it has been suggested to involve interactions between a susceptible genetic background and environmental factors. Studies have shown increased levels of pro-inflammatory cytokines in the peripheral and central nervous system (CNS) of patients with schizophrenia, suggesting an association between immune dysfunction and schizophrenia (Kayser and Dalmau, 2011). Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine that plays an important role in inflammatory and immune responses, including those observed in schizophrenia (Rooney et al., 1995). The TNF gene is located on chromosome 6 within the class III region of HLA, and several single-nucleotide polymorphisms have been identified on its promoter (Allen, 1999). TNF-α 308 A/G (rs1800629), 238 A/G (rs361525), 857 T/C (rs1799724), 863 T/C (rs1800630), and 1031 C/T (rs1799964) are the most commonly studied polymorphisms in schizophrenia. In the present study, we explored whether the TNF-α 308 A/G, 238 A/G, 857 T/C, 863 T/C, and 1031 C/T polymorphisms are associated with susceptibility to schizophrenia using a metaanalysis approach. A literature search was conducted for studies that examined associations between TNF-α polymorphisms and schizophrenia. The MEDLINE and EMBASE citation indexes were used to identify articles, dated up to January 2014, in which the presence of TNF-α polymorphisms was determined in schizophrenia patients and controls. Studies were included in the analysis if they: (1) were case-control studies; (2) included patients with schizophrenia; and (3) included genotype data for the TNF-α polymorphisms. No language restriction was applied. We excluded the following: (1) studies containing overlapping data; (2) studies in which the genotypes could not be ascertained; (3) studies in which family members had been included and the analysis was based on linkage considerations; and (4) studies in which the genotype distribution in controls was not consistent with Hardy–Weinberg equilibrium (HWE), because deviation from HWE among controls suggests the possibility of biased control selection or genotyping errors. Meta-analyses were performed using: (1) allelic contrast; (2) homozygote contrast; (3) recessive models; and (4) dominant models. The point estimates of ORs and their 95% confidence intervals (CIs) were determined for each study. Cochran's Qstatistics were used to assess within- and between-study variations and heterogeneities (Higgins and Thompson, 2002). When a significant Q-statistic indicated heterogeneity across studies, the http://dx.doi.org/10.1016/j.psychres.2015.02.012 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
random effects model was used for the meta-analysis, and when heterogeneity across studies was not indicated, the fixed effect model was used. Fifteen relevant studies met the study inclusion criteria (Dai et al., 2008; Debnath et al., 2013; Duan et al., 2004; Hanninen et al., 2005; Hashimoto et al., 2004; Kampman et al., 2005; Naz et al., 2011; Pae et al., 2003; Riedel et al., 2002; Sacchetti et al., 2007; Shirts et al., 2006; Tsai et al., 2003; Watanabe et al., 2007; Zai et al., 2006; Zhong et al., 2011). One schizophrenia genome-wide association study (GWAS) showing no allelic association between TNF-α 308 A/G (rs1800629), TNF-α 1031 C/T (rs1799964) polymorphisms and schizophrenia (OR ¼0.993, p ¼0.966; OR ¼1.110, p ¼0.226) was not included in this meta-analysis because genotype data were not available (Stefansson et al., 2009). The meta-analysis showed no association between the TNF-α 308 A allele and schizophrenia when all subjects were considered (OR ¼ 1.103, 95% CI ¼0.910– 1.338, P ¼0.318). After stratification by ethnicity, meta-analysis indicated that the TNF-α 308 A allele was not associated with schizophrenia in European and East Asian populations. No association between schizophrenia and the TNF-α 238 A/G and –857 T/C polymorphisms was found by meta-analyses. However, meta-analysis indicated an association between the TNF-α 1031 CC þ CT genotype and schizophrenia in Asian population (OR ¼1.259, 95% CI ¼1.044–1.518, P ¼ 0.016) (Fig. 1). We evaluated publication bias by using Egger's linear regression test (Egger et al., 1997), which measures funnel plot asymmetry using a natural logarithm scale of ORs. Egger's regression test showed no evidence of publication bias in the meta-analysis of the TNF-α polymorphisms (Egger's regression test p-values 4 0.1). Previous studies have shown that the TNF-α 1031 C/T polymorphism might have functional significance (Kesarwani et al., 2009). TNF-α 1031 is a regulatory site for TNF-α transcription, and increased TNF-α gene transcription leads to TNF-α overproduction (Kesarwani et al., 2009). However, whether the association between the TNF-α 1031 C/T polymorphism and schizophrenia susceptibility is due to a causal association or a LD with the true diseasecausing polymorphism remains to be determined. In conclusion, this meta-analysis demonstrates no relationship between TNF-α 308 A/G, 238 A/G, 857 T/C, or 863 T/C polymorphisms and schizophrenia susceptibility, but the TNF-α 1031 C/T polymorphism is associated with the development of schizophrenia in Asians.
Conflict of interest The authors have no financial or non-financial conflict of interest to declare.
522
Letter to the Editor / Psychiatry Research 226 (2015) 521–522
Fig. 1. Forrest plot for the association between the CC þ CT genotype of the TNF-α 1031 A/G polymorphism and schizophrenia in Asian population.
Acknowledgments This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References Allen, R.D., 1999. Polymorphism of the human TNF-alpha promoter – random variation or functional diversity? Molecular Immunology 36, 1017–1027. Dai, J., Ahan, ZH, Cai, GH, Huang, JW, 2008. Association analysis of tumor necrosis factor alpha promoter polymorphisms with schizophrenia. Chinese Journal of Behavioral Medical Science 17, 625–627. Debnath, M., Mitra, B., Bera, N.K., Chaudhuri, T.K., Zhang, Y.P., 2013. Lack of association of IL-6 ( 174G 4C) and TNF-alpha ( 238G 4A) variants with paranoid schizophrenia in Indian Bengalee population. Cytokine 61, 455–458. Duan, S., Xu, Y., Chen, W., Liu, Z., Guo, T., Gao, J., Bian, L., Zheng, Y., Li, X., Zhang, X., Pan, Y., Gu, N., Feng, G., He, L., 2004. No association between the promoter variants of tumor necrosis factor alpha (TNF-alpha) and schizophrenia in Chinese Han population. Neuroscience Letters 366, 139–143. Egger, M., Davey Smith, G., Schneider, M., Minder, C., 1997. Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629–634. Hanninen, K., Katila, H., Rontu, R., Mattila, K.M., Hurme, M., Lehtimaki, T., 2005. Tumor necrosis factor-alpha – G308A polymorphism in schizophrenia in a Finnish population. Neuroscience Letters 385, 76–81. Hashimoto, R., Yoshida, M., Ozaki, N., Yamanouchi, Y., Iwata, N., Suzuki, T., Kitajima, T., Tatsumi, M., Kamijima, K., Kunugi, H., 2004. Association analysis of the 308G4 A promoter polymorphism of the tumor necrosis factor alpha (TNFalpha) gene in Japanese patients with schizophrenia. Journal of Neural Transmission 111, 217–221. Higgins, J.P., Thompson, S.G., 2002. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 21, 1539–1558. Kampman, O., Anttila, S., Illi, A., Mattila, K.M., Rontu, R., Leinonen, E., Lehtimaki, T., 2005. Interaction of tumor necrosis alpha–G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 255, 279–283. Kayser, M.S., Dalmau, J., 2011. The emerging link between autoimmune disorders and neuropsychiatric disease. The Journal of Neuropsychiatry and Clinical Neurosciences 23, 90–97. Kesarwani, P., Mandhani, A., Mittal, R.D., 2009. Polymorphisms in tumor necrosis factor-A gene and prostate cancer risk in North Indian cohort. The Journal of Urology 182, 2938–2943. Naz, M., Riaz, M., Saleem, M., 2011. Potential role of Neuregulin 1 and TNF-alpha (-308) polymorphism in schizophrenia patients visiting hospitals in Lahore, Pakistan. Molecular Biology Reports 38, 4709–4714.
Pae, C.U., Chae, J.H., Bahk, W.M., Han, H., Jun, T.Y., Kim, K.S., Kwon, Y.S., Serretti, A., 2003. Tumor necrosis factor-alpha gene polymorphism at position -308 and schizophrenia in the Korean population. Psychiatry and Clinical Neurosciences 57, 399–403. Riedel, M., Kronig, H., Schwarz, M.J., Engel, R.R., Kuhn, K.U., Sikorski, C., Sokullu, S., Ackenheil, M., Moller, H.J., Muller, N., 2002. No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 252, 232–234. Rooney, M., David, J., Symons, J., Di Giovine, F., Varsani, H., Woo, P., 1995. Inflammatory cytokine responses in juvenile chronic arthritis. British Journal of Rheumatology 34, 454–460. Sacchetti, E., Bocchio-Chiavetto, L., Valsecchi, P., Scassellati, C., Pasqualetti, P., Bonvicini, C., Corsini, P., Rossi, G., Cesana, B.M., Barlati, S., Gennarelli, M., 2007. -G308A tumor necrosis factor alpha functional polymorphism and schizophrenia risk: meta-analysis plus association study. Brain, Behavior, and Immunity 21, 450–457. Shirts, B.H., Bamne, M., Kim, J.J., Talkowski, M., Wood, J., Yolken, R., Nimgaonkar, V.L., 2006. A comprehensive genetic association and functional study of TNF in schizophrenia risk. Schizophrenia Research 83, 7–13. Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., Werge, T., Pietiläinen, O.P., Mors, O., Mortensen, P.B., 2009. Common variants conferring risk of schizophrenia. Nature 460, 744–747. Tsai, S.J., Hong, C.J., Yu, Y.W., Lin, C.H., Liu, L.L., 2003. No association of tumor necrosis factor alpha gene polymorphisms with schizophrenia or response to clozapine. Schizophrenia Research 65, 27–32. Watanabe, Y., Muratake, T., Kaneko, N., Fukui, N., Nara, Y., Someya, T., 2007. No association between the tumor necrosis factor-alpha gene promoter polymorphisms and schizophrenia in a Japanese population. Psychiatry Research 153, 1–6. Zai, G., Muller, D.J., Volavka, J., Czobor, P., Lieberman, J.A., Meltzer, H.Y., Kennedy, J.L., 2006. Family and case-control association study of the tumor necrosis factor-alpha (TNF-alpha) gene with schizophrenia and response to antipsychotic medication. Psychopharmacology 188, 171–182. Zhong, H.J., Peng, L., Zhu, Y.S., Dang, J., Huo, Z.H., 2011. Association of the polymorphisms in the promoter region of tumor necrosis factor alpha and interleukin 6 genes with schizophrenia. Zhonghua yi xue yi chuan xue za zhi ¼Zhonghua yixue yichuanxue zazhi ¼Chinese Journal of Medical Genetics 28, 427–431.
Young Ho Lee n, Gwan Gyu Song Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea E-mail address: [email protected] (Y.H. Lee) Received 30 December 2014 16 February 2015 20 February 2015 Available online 26 February 2015
n Correspondence to: Division of Rheumatology, Department of Internal Medicine, Korea University, Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea. Tel.: þ 82 2 920 5645; fax: þ 82 2 922 5974.
