Association between rs1800795 (-174 G/C) Polymorphism in the Promoter of IL6 Gene and Risk of Relapsing-Remitting Multiple Sclerosis (RRMS) in Isfahan Population
Affiliation(s)
1 Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran. 2 Department of Immunology, Isfahan University of Medical Science, Isfahan, Iran. 3 Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran.
1 Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran. 2 Department of Immunology, Isfahan University of Medical Science, Isfahan, Iran. 3 Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran.
ABSTRACT
Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system (CNS) that mostly affects young adults. The etiology of MS includes both genetic and environmental factors. A single nucleotide polymorphism (SNP) linked with autoimmune disorders predisposition, identified by Genome-Wide Association Study (GWAS) among genes which immunologically related are considerably over signified. The goal of the current study is investigation of the association between rs1800795 (-174 G/C) polymorphism in the promoter of IL6 gene variant with the risk of RRMS in a subset of Iranian population. In this case-control study, 110 healthy subjects and 110 patients with RRMS were included. DNA was extracted from blood samples and polymerase chain reaction (PCR) was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism (RFLP) method was performed for genotyping of the DNA samples with a specific restriction enzyme (NlaIII). SPSS for Windows software (version 18.0; SPSS, Chicago, IL) was used for statistical analysis. No significant differences were found between RRMS patients and healthy controls with respect to the distribution of the cytokine gene polymorphism investigated. Odds ratio adjusted for age, sex, and blood groups (except A blood group) has displayed similar outcomes. These results indicate that the rs1800795 SNP is not a susceptibility gene variant for development of RRMS in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to RRMS.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system (CNS) that mostly affects young adults. The etiology of MS includes both genetic and environmental factors. A single nucleotide polymorphism (SNP) linked with autoimmune disorders predisposition, identified by Genome-Wide Association Study (GWAS) among genes which immunologically related are considerably over signified. The goal of the current study is investigation of the association between rs1800795 (-174 G/C) polymorphism in the promoter of IL6 gene variant with the risk of RRMS in a subset of Iranian population. In this case-control study, 110 healthy subjects and 110 patients with RRMS were included. DNA was extracted from blood samples and polymerase chain reaction (PCR) was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism (RFLP) method was performed for genotyping of the DNA samples with a specific restriction enzyme (NlaIII). SPSS for Windows software (version 18.0; SPSS, Chicago, IL) was used for statistical analysis. No significant differences were found between RRMS patients and healthy controls with respect to the distribution of the cytokine gene polymorphism investigated. Odds ratio adjusted for age, sex, and blood groups (except A blood group) has displayed similar outcomes. These results indicate that the rs1800795 SNP is not a susceptibility gene variant for development of RRMS in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to RRMS.
Cite this paper
Pourhossein, M. , Ghavimi, R. , Alsahebfosoul, F. and Ghaedi, K. (2014) Association between rs1800795 (-174 G/C) Polymorphism in the Promoter of IL6 Gene and Risk of Relapsing-Remitting Multiple Sclerosis (RRMS) in Isfahan Population. Open Journal of Genetics, 4, 407-413. doi: 10.4236/ojgen.2014.45038.
Pourhossein, M. , Ghavimi, R. , Alsahebfosoul, F. and Ghaedi, K. (2014) Association between rs1800795 (-174 G/C) Polymorphism in the Promoter of IL6 Gene and Risk of Relapsing-Remitting Multiple Sclerosis (RRMS) in Isfahan Population. Open Journal of Genetics, 4, 407-413. doi: 10.4236/ojgen.2014.45038.
References
[1] McFarland, H.F. and Martin, R. (2007) Multiple Sclerosis: A Complicated Picture of Autoimmunity. Nature Immunology, 8, 913-919.
http://dx.doi.org/10.1038/ni1507 [2] Confavreux, C., Vukusic, S., Moreau, T. and Adeleine, P. (2000) Relapses and Progression of Disability in Multiple Sclerosis. New England Journal of Medicine, 343, 1430-1438.
http://dx.doi.org/10.1056/NEJM200011163432001 [3] Etemadifar, M. and Maghzi, A.-H. (2011) Sharp Increase in the Incidence and Prevalence of Multiple Sclerosis in Isfahan, Iran. Multiple Sclerosis Journal, 17, 1022-1027.
http://dx.doi.org/10.1177/1352458511401460 [4] Trapp, B.D. and Nave, K.-A. (2008) Multiple Sclerosis: An Immune or Neurodegenerative Disorder? Annual Review of Neuroscience, 31, 247-269.
http://dx.doi.org/10.1146/annurev.neuro.30.051606.094313 [5] Dyment, D.A., Ebers, G.C. and Dessa Sadovnick, A. (2004) Genetics of Multiple Sclerosis. The Lancet Neurology, 3, 104-110.
http://dx.doi.org/10.1016/S1474-4422(03)00663-X [6] Muñoz-Culla, M., Irizar, H. and Otaegui, D. (2013) The Genetics of Multiple Sclerosis: Review of Current and Emerging Candidates. The Application of Clinical Genetics, 6, 63. [7] Hemmer, B., Archelos, J.J. and Hartung, H.-P. (2002) New Concepts in the Immunopathogenesis of Multiple Sclerosis. Nature Reviews Neuroscience, 3, 291-301.
http://dx.doi.org/10.1038/nrn784 [8] Oksenberg, J.R., Baranzini, S.E., Sawcer, S. and Hauser, S.L. (2008) The Genetics of Multiple Sclerosis: SNPs to Pathways to Pathogenesis. Nature Reviews Genetics, 9, 516-526.
http://dx.doi.org/10.1038/nrg2395 [9] Pravica, V., Popadic, D., Savic, E., Markovic, M., Drulovic, J. and Mostarica-Stojkovic, M. (2012) Single Nucleotide Polymorphisms in Multiple Sclerosis: Disease Susceptibility and Treatment Response Biomarkers. Immunologic Research, 52, 42-52.
http://dx.doi.org/10.1007/s12026-012-8273-y [10] Illig, T., Bongardt, F., Schopfer, A., Muller-Scholze, S., Rathmann, W., Koenig, W., Thorand, B., Vollmert, C., Holle, R. and Kolb, H. (2004) Significant Association of the Interleukin-6 Gene Polymorphisms C-174G and A-598G with Type 2 Diabetes. Journal of Clinical Endocrinology & Metabolism, 89, 5053-5058.
http://dx.doi.org/10.1210/jc.2004-0355 [11] Chua, K., Kee, B., Tan, S. and Lian, L. (2009) Interleukin-6 Promoter Polymorphisms (-174 G/C) in Malaysian Patients with Systemic Lupus Erythematosus. Brazilian Journal of Medical and Biological Research, 42, 551-555.
http://dx.doi.org/10.1590/S0100-879X2009000600012 [12] Sfrent-Cornateanu, R., Mihai, C., Balan, S., Ionescu, R. and Moldoveanu, E. (2006) The IL-6 Promoter Polymorphism Is Associated with Disease Activity and Disability in Systemic Sclerosis. Journal of Cellular and Molecular Medicine, 10, 890-895.
http://dx.doi.org/10.2755/jcmm010.004.08 [13] Mirowska-Guzel, D., Gromadzka, G., Mach, A., Czlonkowski, A. and Czlonkowska, A. (2011) Association of IL1A, IL1B, ILRN, IL6, IL10 and TNF-α Polymorphisms with Risk and Clinical Course of Multiple Sclerosis in a Polish Population. Journal of Neuroimmunology, 236, 87-92.
http://dx.doi.org/10.1016/j.jneuroim.2011.04.014 [14] Mihailova, S., Ivanova, M., Mihaylova, A., Quin, L., Mikova, O. and Naumova, E. (2005) Pro- and Anti-Inflammatory Cytokine Gene Polymorphism Profiles in Bulgarian Multiple Sclerosis Patients. Journal of Neuroimmunology, 168, 138-143.
http://dx.doi.org/10.1016/j.jneuroim.2005.06.020 [15] Maimone, D., Guazzi, G.C. and Annunziata, P. (1997) IL-6 Detection in Multiple Sclerosis Brain. Journal of the Neurological Sciences, 146, 59-65.
http://dx.doi.org/10.1016/S0022-510X(96)00283-3 [16] Stelmasiak, Z., Koziol-Montewka, M., Dobosz, B., Rejdak, K., Bartosik-Psujek, H., Mitosek-Szewczyk, K. and Belniak-Legiec, E. (1999) Interleukin-6 Concentration in Serum and Cerebrospinal Fluid in Multiple Sclerosis Patients. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 6, 1104-1108. [17] Ireland, S.J., Blazek, M., Harp, C.T., Greenberg, B., Frohman, E.M., Davis, L.S. and Monson, N.L. (2012) Antibody-Independent B Cell Effector Functions in Relapsing Remitting Multiple Sclerosis: Clues to Increased Inflammatory and Reduced Regulatory B Cell Capacity. Autoimmunity, 45, 400-414.
http://dx.doi.org/10.3109/08916934.2012.665529 [18] Schotte, H., Schlüter, B., Rust, S., Assmann, G., Domschke, W. and Gaubitz, M. (2001) Interleukin-6 Promoter Polymorphism (-174 G/C) in Caucasian German Patients with Systemic Lupus Erythematosus. Rheumatology, 40, 393-400. http://dx.doi.org/10.1093/rheumatology/40.4.393 [19] Schönrock, L.M., Gawlowski, G. and Brück, W. (2000) Interleukin-6 Expression in Human Multiple Sclerosis Lesions. Neuroscience Letters, 294, 45-48.
http://dx.doi.org/10.1016/S0304-3940(00)01543-3 [20] Schulte-Herbrüggen, O., Nassenstein, C., Lommatzsch, M., Quarcoo, D., Renz, H. and Braun, A. (2005) Tumor Necrosis Factor-α and Interleukin-6 Regulate Secretion of Brain-Derived Neurotrophic Factor in Human Monocytes. Journal of Neuroimmunology, 160, 204-209.
http://dx.doi.org/10.1016/j.jneuroim.2004.10.026 [21] Kimura, A. and Kishimoto, T. (2010) IL-6: Regulator of Treg/Th17 Balance. European Journal of Immunology, 40, 1830-1835.
http://dx.doi.org/10.1002/eji.201040391 [22] Hoffjan, S. and Akkad, D.A. (2010) The Genetics of Multiple Sclerosis: An Update 2010. Molecular and Cellular Probes, 24, 237-243.
http://dx.doi.org/10.1016/j.mcp.2010.04.006 [23] Sospedra, M. and Martin, R. (2005) Immunology of Multiple Sclerosis. Annual Review of Immunology, 23, 683-747.
http://dx.doi.org/10.1146/annurev.immunol.23.021704.115707
[1] McFarland, H.F. and Martin, R. (2007) Multiple Sclerosis: A Complicated Picture of Autoimmunity. Nature Immunology, 8, 913-919.
http://dx.doi.org/10.1038/ni1507 [2] Confavreux, C., Vukusic, S., Moreau, T. and Adeleine, P. (2000) Relapses and Progression of Disability in Multiple Sclerosis. New England Journal of Medicine, 343, 1430-1438.
http://dx.doi.org/10.1056/NEJM200011163432001 [3] Etemadifar, M. and Maghzi, A.-H. (2011) Sharp Increase in the Incidence and Prevalence of Multiple Sclerosis in Isfahan, Iran. Multiple Sclerosis Journal, 17, 1022-1027.
http://dx.doi.org/10.1177/1352458511401460 [4] Trapp, B.D. and Nave, K.-A. (2008) Multiple Sclerosis: An Immune or Neurodegenerative Disorder? Annual Review of Neuroscience, 31, 247-269.
http://dx.doi.org/10.1146/annurev.neuro.30.051606.094313 [5] Dyment, D.A., Ebers, G.C. and Dessa Sadovnick, A. (2004) Genetics of Multiple Sclerosis. The Lancet Neurology, 3, 104-110.
http://dx.doi.org/10.1016/S1474-4422(03)00663-X [6] Muñoz-Culla, M., Irizar, H. and Otaegui, D. (2013) The Genetics of Multiple Sclerosis: Review of Current and Emerging Candidates. The Application of Clinical Genetics, 6, 63. [7] Hemmer, B., Archelos, J.J. and Hartung, H.-P. (2002) New Concepts in the Immunopathogenesis of Multiple Sclerosis. Nature Reviews Neuroscience, 3, 291-301.
http://dx.doi.org/10.1038/nrn784 [8] Oksenberg, J.R., Baranzini, S.E., Sawcer, S. and Hauser, S.L. (2008) The Genetics of Multiple Sclerosis: SNPs to Pathways to Pathogenesis. Nature Reviews Genetics, 9, 516-526.
http://dx.doi.org/10.1038/nrg2395 [9] Pravica, V., Popadic, D., Savic, E., Markovic, M., Drulovic, J. and Mostarica-Stojkovic, M. (2012) Single Nucleotide Polymorphisms in Multiple Sclerosis: Disease Susceptibility and Treatment Response Biomarkers. Immunologic Research, 52, 42-52.
http://dx.doi.org/10.1007/s12026-012-8273-y [10] Illig, T., Bongardt, F., Schopfer, A., Muller-Scholze, S., Rathmann, W., Koenig, W., Thorand, B., Vollmert, C., Holle, R. and Kolb, H. (2004) Significant Association of the Interleukin-6 Gene Polymorphisms C-174G and A-598G with Type 2 Diabetes. Journal of Clinical Endocrinology & Metabolism, 89, 5053-5058.
http://dx.doi.org/10.1210/jc.2004-0355 [11] Chua, K., Kee, B., Tan, S. and Lian, L. (2009) Interleukin-6 Promoter Polymorphisms (-174 G/C) in Malaysian Patients with Systemic Lupus Erythematosus. Brazilian Journal of Medical and Biological Research, 42, 551-555.
http://dx.doi.org/10.1590/S0100-879X2009000600012 [12] Sfrent-Cornateanu, R., Mihai, C., Balan, S., Ionescu, R. and Moldoveanu, E. (2006) The IL-6 Promoter Polymorphism Is Associated with Disease Activity and Disability in Systemic Sclerosis. Journal of Cellular and Molecular Medicine, 10, 890-895.
http://dx.doi.org/10.2755/jcmm010.004.08 [13] Mirowska-Guzel, D., Gromadzka, G., Mach, A., Czlonkowski, A. and Czlonkowska, A. (2011) Association of IL1A, IL1B, ILRN, IL6, IL10 and TNF-α Polymorphisms with Risk and Clinical Course of Multiple Sclerosis in a Polish Population. Journal of Neuroimmunology, 236, 87-92.
http://dx.doi.org/10.1016/j.jneuroim.2011.04.014 [14] Mihailova, S., Ivanova, M., Mihaylova, A., Quin, L., Mikova, O. and Naumova, E. (2005) Pro- and Anti-Inflammatory Cytokine Gene Polymorphism Profiles in Bulgarian Multiple Sclerosis Patients. Journal of Neuroimmunology, 168, 138-143.
http://dx.doi.org/10.1016/j.jneuroim.2005.06.020 [15] Maimone, D., Guazzi, G.C. and Annunziata, P. (1997) IL-6 Detection in Multiple Sclerosis Brain. Journal of the Neurological Sciences, 146, 59-65.
http://dx.doi.org/10.1016/S0022-510X(96)00283-3 [16] Stelmasiak, Z., Koziol-Montewka, M., Dobosz, B., Rejdak, K., Bartosik-Psujek, H., Mitosek-Szewczyk, K. and Belniak-Legiec, E. (1999) Interleukin-6 Concentration in Serum and Cerebrospinal Fluid in Multiple Sclerosis Patients. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 6, 1104-1108. [17] Ireland, S.J., Blazek, M., Harp, C.T., Greenberg, B., Frohman, E.M., Davis, L.S. and Monson, N.L. (2012) Antibody-Independent B Cell Effector Functions in Relapsing Remitting Multiple Sclerosis: Clues to Increased Inflammatory and Reduced Regulatory B Cell Capacity. Autoimmunity, 45, 400-414.
http://dx.doi.org/10.3109/08916934.2012.665529 [18] Schotte, H., Schlüter, B., Rust, S., Assmann, G., Domschke, W. and Gaubitz, M. (2001) Interleukin-6 Promoter Polymorphism (-174 G/C) in Caucasian German Patients with Systemic Lupus Erythematosus. Rheumatology, 40, 393-400. http://dx.doi.org/10.1093/rheumatology/40.4.393 [19] Schönrock, L.M., Gawlowski, G. and Brück, W. (2000) Interleukin-6 Expression in Human Multiple Sclerosis Lesions. Neuroscience Letters, 294, 45-48.
http://dx.doi.org/10.1016/S0304-3940(00)01543-3 [20] Schulte-Herbrüggen, O., Nassenstein, C., Lommatzsch, M., Quarcoo, D., Renz, H. and Braun, A. (2005) Tumor Necrosis Factor-α and Interleukin-6 Regulate Secretion of Brain-Derived Neurotrophic Factor in Human Monocytes. Journal of Neuroimmunology, 160, 204-209.
http://dx.doi.org/10.1016/j.jneuroim.2004.10.026 [21] Kimura, A. and Kishimoto, T. (2010) IL-6: Regulator of Treg/Th17 Balance. European Journal of Immunology, 40, 1830-1835.
http://dx.doi.org/10.1002/eji.201040391 [22] Hoffjan, S. and Akkad, D.A. (2010) The Genetics of Multiple Sclerosis: An Update 2010. Molecular and Cellular Probes, 24, 237-243.
http://dx.doi.org/10.1016/j.mcp.2010.04.006 [23] Sospedra, M. and Martin, R. (2005) Immunology of Multiple Sclerosis. Annual Review of Immunology, 23, 683-747.
http://dx.doi.org/10.1146/annurev.immunol.23.021704.115707