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A gender-specific association of interleukin 1 receptor antagonist polymorphism with schizophrenia susceptibility

Published online by Cambridge University Press:  08 March 2013

Mouna Ben Nejma
Affiliation:
Superior Institute of Biotechnology, Monastir University, 5019 Monastir, Tunisia
Ines Zaabar
Affiliation:
Superior Institute of Biotechnology, Monastir University, 5019 Monastir, Tunisia
Ferid Zaafrane
Affiliation:
Psychosis Vulnerability Laboratory CHU F. Bourguiba, Monastir University, Monastir, Tunisia
Sihem Thabet
Affiliation:
Superior Institute of Biotechnology, Monastir University, 5019 Monastir, Tunisia
Anouar Mechri
Affiliation:
Psychosis Vulnerability Laboratory CHU F. Bourguiba, Monastir University, Monastir, Tunisia
Lotfi Gaha
Affiliation:
Psychosis Vulnerability Laboratory CHU F. Bourguiba, Monastir University, Monastir, Tunisia
Kamel Ben Salem
Affiliation:
Department of Epidemiology and Preventive Medicine, CHU F. Bourguiba, Monastir University, Monastir, Tunisia
Besma Bel Hadj Jrad*
Affiliation:
Superior Institute of Biotechnology, Monastir University, 5019 Monastir, Tunisia
*
Besma Bel Hadj Jrad, Superior Institute of Monastir Biotechnology, Monastir University, Monastir 5019, Tunisie. Tel: +216 73 465 405; Fax: +216 73 465 404; E-mail: bbhj2002@yahoo.fr

Abstract

Objective

Recent genetic studies have revealed that the interleukin (IL) 1 gene complex is associated with schizophrenia in the Caucasian population; however, data from the North African population are limited. To further assess the role of interleukin 1 receptor antagonist protein (IL1Ra) in schizophrenia, we examined a functional multiallelic polymorphism localised in intron 2 of this receptor gene associated with an altered level of IL1Ra.

Methods

In the present case–control study, we have analysed the (86 bp)n polymorphism of the interleukin 1 receptor antagonist (IL1RN) gene (RS 1794068) by polymerase chain reaction genotyping in 259 patients with schizophrenia and 178 healthy controls from the Tunisian population.

Results

We showed that the frequencies of the IL1RN*2/2 genotype and allele 2 were higher in the patient group compared with the control group, and the difference was statistically significant [13.5% vs. 5.6%, p = 10−3, odds ratio (OR) = 3.2% and 32.8% vs. 21.9%, p = 3 × 10−4, OR = 1.76, respectively). When we evaluated the association between this genetic polymorphism and the clinical variables of schizophrenia, we found that the frequencies of the 2/2 genotype and allele 2 were significantly higher in the male patient group (p = 10−4 and 10−5, respectively) compared with the male control group, indicating a substantially increased risk for sex-onset schizophrenia with inheritance of the IL1RN2 allele. When the association between the genotypes and outcome was evaluated by multiple logistic regression analysis, the adjusted OR for the IL1RN genotypes remained statistically significant [1.39; 95% confidence interval (CI) = 1.11–1.73; p = 0.003].

Conclusion

The intron 2 polymorphism in IL1RN or a genetic polymorphism at proximity seems to be associated specifically with schizophrenia in the Tunisian male population.

Type
Original Articles
Copyright
Copyright © Scandinavian College of Neuropsychopharmacology 2013 

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References

1.Liddle, PF. The symptoms of chronic schizophrenia: a re-examination of the positive–negative dichotomy. Br J Psychiatry 1987;151:145151.CrossRefGoogle ScholarPubMed
2.Mueser, KT, McGurk, SR. Schizophrenia. Lancet 2004;363:20632072.CrossRefGoogle ScholarPubMed
3.McGrath, JJ. Variations in the incidence of schizophrenia: data versus dogma. Schizophr Bull 2006;32:195197.CrossRefGoogle ScholarPubMed
4.Angermeyer, MC, Kuhn, L, Goldstein, JM. Gender and the course of schizophrenia: differences in treated outcome. Schizophr Bull 1990;16:293307.CrossRefGoogle Scholar
5.Harrison, PJ, Weinberger, DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10:4068.CrossRefGoogle ScholarPubMed
6.Potvin, S, Stip, E, Sepehry, AA, Gendron, A, Bah, R, Kouassi, E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 2008;63:801808.CrossRefGoogle ScholarPubMed
7.Nawa, H, Takahashi, M, Patterson, PH. Cytokine and growth factor involvement in schizophrenia – support for the developmental model. Mol Psychiatry 2000;5:594603. Review.CrossRefGoogle ScholarPubMed
8.Wright, P, Gill, M, Murray, RM. Schizophrenia: genetics and the maternal immune response to viral infection. Am J Med Genet 1993;48:4046. Review.CrossRefGoogle ScholarPubMed
9.Tohmi, M, Tsuda, N, Watanabe, Y, Kakita, A, Nawa, H. Perinatal inflammatory cytokine challenge results in distinct neurobehavioral alterations in rats: implication in psychiatric disorders of developmental origin. Neurosci Res 2004;50:6775.CrossRefGoogle ScholarPubMed
10.Giulian, D, Young, DG, Woodward, J, Brown, DC, Lachman, LB. Interleukin-1 is an astroglial growth factor in the developing brain. J Neurosci 1988;8:709714.CrossRefGoogle ScholarPubMed
11.Potter, ED, Ling, ZD, Carvey, PM. Cytokine-induced conversion of mesencephalic-derived progenitor cells into dopamine neurons. Cell Tissue Res 1999;296:235246.CrossRefGoogle ScholarPubMed
12.Allan, SM, Tyrrell, PJ, Rothwell, NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol 2005;5:629640. Review.CrossRefGoogle ScholarPubMed
13.Katila, H, Appelberg, B, Hurme, M, Rimón, R. Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders. Schizophr Res 1994;12:2934.CrossRefGoogle ScholarPubMed
14.Theodoropoulou, S, Spanakos, G, Baxevanis, CNet al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 2001;47:1325.CrossRefGoogle ScholarPubMed
15.Akiyama, K. Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophr Res 1999;37:97106.CrossRefGoogle ScholarPubMed
16.Arend, WP, Guthridge, CJ. Biological role of interleukin 1 receptor antagonist isoforms. Ann Rheum Dis 2000;59(Suppl. 1):i60i64.CrossRefGoogle ScholarPubMed
17.Witkin, SS, Gerber, S, Ledger, WJ. Influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin Infect Dis 2002;34:204209. Review.CrossRefGoogle ScholarPubMed
18.Santtila, S, Savinainen, K, Hurme, M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol 1998;47:195198.CrossRefGoogle ScholarPubMed
19.Andus, T, Daig, R, Vogl, Det al. Imbalance of the interleukin 1 system in colonic mucosa – association with intestinal inflammation and interleukin 1 receptor antagonist [corrected] genotype 2. Gut 1997;41:651657.CrossRefGoogle ScholarPubMed
20.Dewberry, R, Holden, H, Crossman, D, Francis, S. Interleukin-1 receptor antagonist expression in human endothelial cells and atherosclerosis. Arterioscler Thromb Vasc Biol 2000;20:23942400.CrossRefGoogle ScholarPubMed
21.Carter, MJ, Jones, S, Camp, NJet al. Functional correlates of the interleukin-1 receptor antagonist gene polymorphism in the colonic mucosa in ulcerative colitis. Genes Immun 2004;5:815.CrossRefGoogle ScholarPubMed
22.Papiol, S, Molina, V, Desco, Met al. Ventricular enlargement in schizophrenia is associated with a genetic polymorphism at the interleukin-1 receptor antagonist gene. Neuroimage 2005;27:10021006.CrossRefGoogle ScholarPubMed
23.Segman, RH, Meltzer, A, Gross-Tsur, Vet al. Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder. Mol Psychiatry 2002;7:7274.CrossRefGoogle ScholarPubMed
24.Xu, M, He, L. Convergent evidence shows a positive association of interleukin-1 gene complex locus with susceptibility to schizophrenia in the Caucasian population. Schizophr Res 2010;1–3:131142.CrossRefGoogle Scholar
25.Watanabe, Y, Nunokawa, A, Kaneko, N, Muratake, T, Koizumi, M, Someya, T. Lack of association between the interleukin-1 gene complex and schizophrenia in a Japanese population. Psychiatry Clin Neurosci 2007;61:364369.CrossRefGoogle Scholar
26.Shirts, BH, Wood, J, Yolken, RH, Nimgaonkar, VL. Association study of IL10, IL1beta, and IL1RN and schizophrenia using tag SNPs from a comprehensive database: suggestive association with rs16944 at IL1beta. Schizophr Res 2006;88:235244.CrossRefGoogle ScholarPubMed
27.Papiol, S, Rosa, A, Gutiérrez, Bet al. Interleukin-1 cluster is associated with genetic risk for schizophrenia and bipolar disorder. J Med Genet 2004;41:219223.CrossRefGoogle ScholarPubMed
28.Kim, SJ, Lee, HJ, Koo, HGet al. Impact of IL-1 receptor antagonist gene polymorphism on schizophrenia and bipolar disorder. Psychiatr Genet 2004;14:165167.CrossRefGoogle ScholarPubMed
29.Zanardini, R, Bocchio-Chiavetto, L, Scassellati, Cet al. Association between IL-1beta-511C/T and IL-1RA (86 bp)n repeats polymorphisms and schizophrenia. J Psychiatr Res 2003;37:457462.CrossRefGoogle Scholar
30.Katila, H, Hänninen, K, Hurme, M. Polymorphisms of the interleukin-1 gene complex in schizophrenia. Mol Psychiatry 1999;4:179181.CrossRefGoogle ScholarPubMed
31.American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV TR), 4th edn.Washington, DC: American Psychiatric Association, 1994.Google Scholar
32.Wing, JK, Babor, T, Burke, Jet al. SCAN. Schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiatry 1990;47:589593.CrossRefGoogle ScholarPubMed
33.Tarlow, JK, Blakemore, AI, Lennard, Aet al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 1993;91:403404.CrossRefGoogle ScholarPubMed
34.Chowdari, KV, Xu, K, Zhang, Fet al. Immune related genetic polymorphisms and schizophrenia among the Chinese. Hum Immunol 2001;62:714724.CrossRefGoogle ScholarPubMed
35.Toyooka, K, Watanabe, Y, Iritani, Set al. A decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of schizophrenic patients. Neurosci Res 2003;46:299307.CrossRefGoogle ScholarPubMed
36.Prolo, P, Licinio, J. Cytokines in affective disorders and schizophrenia: new clinical and genetic findings. Mol Psychiatry 1999;4:109111.CrossRefGoogle ScholarPubMed
37.Spulber, S, Bartfai, T, Schultzberg, M. IL-1/IL-1ra balance in the brain revisited – evidence from transgenic mouse models. Brain Behav Immun 2009;23:573579. Review.CrossRefGoogle ScholarPubMed
38.Spulber, S, Oprica, M, Bartfai, T, Winblad, B, Schultzberg, M. Blunted neurogenesis and gliosis due to transgenic overexpression of human soluble IL-1ra in the mouse. Eur J Neurosci 2008;27:549558.CrossRefGoogle ScholarPubMed
39.Marx, CE, Jarskog, LF, Lauder, JM, Lieberman, JA, Gilmore, JH. Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia. Biol Psychiatry 2001;50:743749.CrossRefGoogle ScholarPubMed
40.Meisenzahl, EM, Rujescu, D, Kirner, Aet al. Association of an interleukin-1b genetic polymorphism with altered brain structure in patients with schizophrenia. Am J Psychiatry 2001;158:13161319.CrossRefGoogle Scholar
41.Cullup, H, Middleton, PG, Duggan, G, Conn, JS, Dickinson, AM. Environmental factors and not genotype influence the plasma level of interleukin-1 receptor antagonist in normal individuals. Clin Exp Immunol 2004;137:351358.CrossRefGoogle Scholar
42.Lynch, EA, Dinarello, CA, Cannon, JG. Gender differences in IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist secretion from mononuclear cells and urinary excretion. J Immunol 1994;153:300306.CrossRefGoogle ScholarPubMed
43.Sadeghi, M, Daniel, V, Naujokat, C, Weimer, R, Opelz, G. Strikingly higher interleukin (IL)-1alpha, IL-1beta and soluble interleukin-1 receptor antagonist (sIL-1RA) but similar IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and interferon IFN-gamma urine levels in healthy females compared to healthy males: protection against urinary tract injury? Clin Exp Immunol 2005;142:312317.CrossRefGoogle ScholarPubMed
44.Kulkarni, J. Oestrogen – a new treatment approach for schizophrenia? Med J Aust 2009;190:S37S38.CrossRefGoogle ScholarPubMed