The TNF-Alpha Gene −1031T>C Polymorphism Is Associated With Onset Age but Not With Risk of Schizophrenia in a Chinese Population

Objective: Evidence has shown the importance of tumor necrosis factor alpha (TNF-alpha) in the pathophysiological feature in schizophrenia patients. This study aims to determine the impact of a single-nucleotide polymorphism (SNP) in the TNF-alpha gene promoter on the susceptibility, onset age, and cognitive function of schizophrenia. Method: The SNP −1031T>C in the TNF-alpha gene was genotyped in 905 patients and 571 healthy controls. The Positive and Negative Syndrome Scale (PANSS) was used to assess the schizophrenia symptoms and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognitive function. Results: There was no significant difference in allele or genotype distribution of the SNP −1031T>C between patients and controls (p = .85, p = .98). This polymorphism had no significant genotypic effect on the symptomatology assessed by the PANSS. Interestingly, this polymorphism was significantly correlated with onset age in schizophrenia patients (p = .004). We found an earlier onset age in patients with the TT genotype compared to those with the CT and CC genotypes (both p < .05). Moreover, there were significant genotypic effects on the immediate memory index, visuospatial/constructional index, and RBANS total score (all p < 0.05) in the patient group. Conclusions: Our results suggest that the SNP −1031T>C of the TNF-alpha gene may not be associated with susceptibility to schizophrenia but possibly acts as a modulator for its onset age as well as for cognitive deficits.

[1]  A. Al-Asmari,et al.  Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with schizophrenia , 2017, Neuropsychiatric disease and treatment.

[2]  D. Goldsmith,et al.  A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression , 2016, Molecular Psychiatry.

[3]  Haibing Zhu,et al.  The reduction of CSF tumor necrosis factor alpha levels in schizophrenia: no correlations with psychopathology and coincident metabolic characteristics , 2016, Neuropsychiatric disease and treatment.

[4]  A. McAllister,et al.  Maternal immune activation: Implications for neuropsychiatric disorders , 2016, Science.

[5]  J. Soares,et al.  Serum IL-18 level, clinical symptoms and IL-18-607A/C polymorphism among chronic patients with schizophrenia in a Chinese Han population , 2016, Psychoneuroendocrinology.

[6]  R. Dantzer,et al.  Is there a role for immune-to-brain communication in schizophrenia? , 2016, Psychopharmacology.

[7]  Giulio Genovese,et al.  Schizophrenia risk from complex variation of complement component 4 , 2016, Nature.

[8]  S. Koçbiyik,et al.  The role of tumour necrosis factor alpha and soluble tumour necrosis factor alpha receptors in the symptomatology of schizophrenia , 2016, Nordic journal of psychiatry.

[9]  L. Tian,et al.  Increased IL-3 serum levels in chronic patients with schizophrenia: Associated with psychopathology , 2015, Psychiatry Research.

[10]  O. P. Kalra,et al.  Association of tumor necrosis factor (TNF) promoter polymorphisms with plasma TNF-α levels and susceptibility to diabetic nephropathy in North Indian population. , 2015, Journal of diabetes and its complications.

[11]  J. Soares,et al.  Reduced serum TNF alpha level in chronic schizophrenia patients with or without tardive dyskinesia , 2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[12]  N. Barnes,et al.  Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis , 2014, Schizophrenia Research.

[13]  Alan S. Brown,et al.  The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies , 2014, Biological Psychiatry.

[14]  LuShun Zhang,et al.  Lack of association between TNFα rs1800629 polymorphism and schizophrenia risk: A meta-analysis , 2013, Psychiatry Research.

[15]  L. Ellman,et al.  Inflammatory Cytokines and Neurological and Neurocognitive Alterations in the Course of Schizophrenia , 2013, Biological Psychiatry.

[16]  A. Altamura,et al.  Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology , 2013, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[17]  T. Kosten,et al.  Elevated interleukin-18 serum levels in chronic schizophrenia: Association with psychopathology. , 2012, Journal of psychiatric research.

[18]  Q. Pittman,et al.  Cytokines and brain excitability , 2012, Frontiers in Neuroendocrinology.

[19]  B. Kirkpatrick,et al.  Meta-Analysis of Cytokine Alterations in Schizophrenia: Clinical Status and Antipsychotic Effects , 2011, Biological Psychiatry.

[20]  P. Belmonte-de-Abreu,et al.  Increased annexin-V and decreased TNF-alpha serum levels in chronic-medicated patients with schizophrenia , 2011, Neuroscience Letters.

[21]  D. Song,et al.  Association of tumor necrosis factor-α (TNF-α) promoter polymorphisms with overweight/obesity in a Korean population , 2011, Inflammation Research.

[22]  M. Talebi,et al.  Genetic association of TNF-α-308 G/A and -863 C/A polymorphisms with late onset Alzheimer's disease in Azeri Turk population of Iran , 2011, Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences.

[23]  Inbal Goshen,et al.  Immune modulation of learning, memory, neural plasticity and neurogenesis , 2011, Brain, Behavior, and Immunity.

[24]  Liang Liu,et al.  Tyrosine hydroxylase, interleukin-1β and tumor necrosis factor-α are overexpressed in peripheral blood mononuclear cells from schizophrenia patients as determined by semi-quantitative analysis , 2010, Psychiatry Research.

[25]  J. Hauser,et al.  Association of Tumor Necrosis Factor –308G/A Promoter Polymorphism with Schizophrenia and Bipolar Affective Disorder in a Polish Population , 2008, Neuropsychobiology.

[26]  Emmanuel Stip,et al.  Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review , 2008, Biological Psychiatry.

[27]  V. Álvarez,et al.  Vesicoureteric reflux and tumor necrosis factor-alpha gene polymorphism. , 2007, Journal of pediatric urology.

[28]  F. Ferro,et al.  Cytokines and the Brain , 2004, International journal of immunopathology and pharmacology.

[29]  S. Duan,et al.  No association between the promoter variants of tumor necrosis factor alpha (TNF-α) and schizophrenia in Chinese Han population , 2004, Neuroscience Letters.

[30]  M. Rietschel,et al.  Association of tumor necrosis factor alpha gene -G308A polymorphism with schizophrenia , 2003, Schizophrenia Research.

[31]  Y. Teo,et al.  Tumor necrosis factor-α gene promoter polymorphisms in chronic schizophrenia , 2003, Biological Psychiatry.

[32]  N. Hayward,et al.  Tumor necrosis factor haplotype analysis amongst schizophrenia probands from four distinct populations in the Asia‐Pacific region , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[33]  A. Serretti,et al.  Tumor necrosis factor‐α gene polymorphism at position −308 and schizophrenia in the Korean population , 2003, Psychiatry and clinical neurosciences.

[34]  H. Möller,et al.  No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia , 2002, European Archives of Psychiatry and Clinical Neuroscience.

[35]  A. Hajeer,et al.  Influence of TNFa gene polymorphisms on TNFa production and disease , 2001 .

[36]  M. Owen,et al.  A genomewide linkage study of age at onset in schizophrenia. , 2001, American journal of medical genetics.

[37]  A. Madej,et al.  Neuroleptics normalize increased release of interleukin-1β and tumor necrosis factor-α from monocytes in schizophrenia , 2001, Schizophrenia Research.

[38]  H. Herken,et al.  Research Paper Mediators of Inflammation, 10, 109–115 (2001) ACTIVAT ION of the inflammatory response system and , 2022 .

[39]  M. Clerici,et al.  Cytokine profiles in drug-naive schizophrenic patients , 2001, Schizophrenia Research.

[40]  C. Stefanis,et al.  Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients , 2001, Schizophrenia Research.

[41]  D. Remick,et al.  Cytokines and the brain: implications for clinical psychiatry. , 2000, The American journal of psychiatry.

[42]  C. Randolph,et al.  The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. , 1998, Journal of clinical and experimental neuropsychology.

[43]  J. P. Schwartz,et al.  Involvement of cytokines in normal CNS development and neurological diseases: Recent progress and perspectives , 1998, Journal of neuroscience research.

[44]  M. Ackenheil,et al.  Psychoneuroimmunology and the cytokine action in the CNS: Implications for psychiatric disorders , 1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[45]  J. Mege,et al.  A differential role for interleukin-6 and tumor necrosis factor-α in schizophrenia? , 1997, Schizophrenia Research.

[46]  H. Mcdevitt,et al.  Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Straub,et al.  The putative schizophrenia locus on chromosome 6p: a brief overview of the linkage studies. , 1996, Molecular psychiatry.

[48]  J. Calabrese,et al.  Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. , 1995, Journal of psychiatric research.

[49]  G. Zunta-Soares,et al.  Decreased serum TNF-alpha levels in chronic schizophrenia patients on long-term antipsychotics: correlation with psychopathology and cognition , 2014, Psychopharmacology.

[50]  C. Randolph,et al.  Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) , 2009 .

[51]  C. Haile,et al.  Tumour necrosis factor alpha polymorphism (-1031T/C) is associated with age of onset of schizophrenia. , 2005, Molecular Psychiatry.

[52]  S. Duan,et al.  No association between the promoter variants of tumor necrosis factor alpha (TNF-alpha) and schizophrenia in Chinese Han population. , 2004, Neuroscience letters.

[53]  L. N. Valenti,et al.  TNFalpha promoter polymorphisms. , 2004, Methods in molecular medicine.

[54]  L. N. Valenti,et al.  TNFα Promoter Polymorphisms , 2004 .

[55]  Y. Teo,et al.  Tumor necrosis factor-alpha gene promoter polymorphisms in chronic schizophrenia. , 2003, Biological psychiatry.

[56]  A. Mansur,et al.  Analysis of a polymorphism in the promoter region of the tumor necrosis factor alpha gene in schizophrenia and bipolar disorder: further support for an association with schizophrenia , 2003, Molecular Psychiatry.

[57]  R. Malenka,et al.  Control of synaptic strength by glial TNFalpha. , 2002, Science.

[58]  R. Pioli,et al.  Association between −G308A tumor necrosis factor alpha gene polymorphism and schizophrenia , 2001, Molecular Psychiatry.

[59]  A. Madej,et al.  Neuroleptics normalize increased release of interleukin- 1 beta and tumor necrosis factor-alpha from monocytes in schizophrenia. , 2001, Schizophrenia research.

[60]  A. Hajeer,et al.  Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. , 2001, Human immunology.

[61]  樋口 貴文 Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-α gene in Japanese , 1999 .

[62]  A. Kimura,et al.  Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. , 1998, Tissue antigens.

[63]  J. Mege,et al.  A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? , 1997, Schizophrenia Research.