TNF-α Genetic Polymorphisms and its Expression in Egyptian Rheumatoid Arthritis Patients
American Journal of Life Sciences
Volume 2, Issue 4, August 2014, Pages: 234-240
Received: Aug. 15, 2014; Accepted: Aug. 23, 2014; Published: Aug. 30, 2014
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Afaf K. Mousa, Zoology Department, Faculty of Science, Damietta University, New Damietta, Egypt
Ahmed M. Ghoneim, Zoology Department, Faculty of Science, Damietta University, New Damietta, Egypt
Noha B. El-Mashad, Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Ahmed E. El-Ghobashy, Zoology Department, Faculty of Science, Damietta University, New Damietta, Egypt
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Rheumatoid arthritis (RA) is a complex, multifactorial, inflammatory disease that affects more than 1.5 million adults. The current study aimed to investigate whether there is an association between either -376 G/A or -238 G/A polymorphisms of TNF-α promoter and the risk of RA in Egyptian patients, and investigate whether these polymorphisms are linked to TNF-α expression. DNA from 54 clinically confirmed RA patients and 24 apparently healthy individuals was genotyped by RFLP technique. Some samples were selected for semi-quantitative measurement of TNF-α mRNA expression. For the -376 polymorphism, no polymorphism was recorded in this site neither in RA patients nor in the apparently healthy individuals. This indicated the wide distribution of the wild type GG genotype among Egyptians. For the -238 G/A polymorphism, data indicated that 77.8% of RA patients were of the genotype GG and 22.2% were heterozygous (GA), while 91.7% of the apparently healthy individuals were of the genotype GG and 8.3% were heterozygous (GA). The homozygous genotype AA was not recorded in any RA or healthy subject. There was no statistically significant difference in the genotype distribution between RA patients and the apparently healthy individuals. Also, there was no statistically significant difference in either the G or A allele distribution between the RA group and the group of healthy subjects. Semi-quantitative PCR on some samples revealed a statistically significant increase in the relative expression of TNF-α mRNA in RA patients compared to healthy subjects. Based on these data, we conclude that -238 G/A and -376 G/A polymorphisms can not be considered as risk factors for RA among Egyptians and the increased expression of TNF-α in Egyptian RA patients is not linked to these polymorphisms. Therefore, Egyptian RA patients may have different genetic or environmental factors contributing to the pathogenesis of RA and further studies are necessary to search for other genetic polymorphisms and/or genes that contribute to the increased expression of TNF-α and hence the pathogenesis of RA in Egyptian patients.
TNF-α, Cytokine, Polymorphism, Expression, Susceptibility, Rheumatoid Arthritis
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Afaf K. Mousa, Ahmed M. Ghoneim, Noha B. El-Mashad, Ahmed E. El-Ghobashy, TNF-α Genetic Polymorphisms and its Expression in Egyptian Rheumatoid Arthritis Patients, American Journal of Life Sciences. Vol. 2, No. 4, 2014, pp. 234-240. doi: 10.11648/j.ajls.20140204.17
E. Choy, "Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis," Rheumatology, vol. 51, pp. 3-11, 2012.
Centers for Disease Control and Prevention. Rheumatoid arthritis.
Arthritis Foundation. News from the Arthritis Foundation: Rheumatoid Arthritis Fact Sheet. 2008.
C. S. Crowson, E. L. Matteson, E. Myasoedova, C. J. Michet, F. C. Ernste, K. J. Warrington, J. M. Davis III, G. G. Hunder, T. M. Therneau, and S. E. Gabriel, "The Lifetime Risk of Adult-Onset Rheumatoid Arthritis and Other Inflammatory Autoimmune Rheumatic Diseases," Arthritis Rheum., vol. 63, pp. 633-639, 2011.
J. D. Reveille, "The genetic contribution to the pathogenesis of rheumatoid arthritis," Curr. Opin. Rheumatol., vol. 10, pp. 187–200, 1998.
J. S. Smolen, and G. Steiner, "Therapeutic strategies for rheumatoid arthritis," Nat. Rev. Drug Discov., vol. 2, pp. 473-88, 2003.
J. S. Smolen, D. Aletaha, M. Koeller, M. H. Weisman, and P. Emery, "New therapies for treatment of rheumatoid arthritis," Lancet, vol. 370, pp. 1861-74, 2007.
F. M. Brennan, R. N. Maini, and M. Feldmann, "TNF alpha–a pivotal role in rheumatoid arthritis?," Br. J. Rheumatol., vol. 31, pp. 293-298, 1992.
P. Nemec, P. Monika, S. Martina, V. Anna, S. Miroslav, and G. Jindra, "Polymorphism in the tumor necrosis factor-α gene promoter is associated with severity of rheumatoid arthritis in the Czech population," Clin. Rheumatol., vol. 27, pp. 59-65, 2008.
M. W. Van der Linden, T. W. Huizinga, D. J. Stoeken, A. Sturk, and R. G. Westendorp, "Determination of tumour necrosis factor-alpha and interleukin-10 production in a whole blood stimulation system: assessment of laboratory error and individual variation," J. Immunol. Methods, vol. 218, pp. 63-71, 1998.
J. P. Bayley, T. H. Ottenhoff, and C. L. Verweij, "Is there a future for TNF promoter polymorphisms?" Genes Immun., vol. 5, pp. 315-329, 2004.
C. L. Verweij, "Tumour necrosis factor gene polymorphisms as severity markers in rheumatoid arthritis," Ann. Rheum. Dis., vol. 58, pp. I20-I26, 1999.
N. de Vries, and P. P. Tak, "The response to anti-TNF-alpha treatment: gene regulation at the bedside," Rheumatology, vol. 44, pp. 705-707, 2005.
J. E. Fonseca, T. Carvalho, M. Cruz, P. Nero, M. Sobral, A.F. Mourão, J. Cavaleiro, D. Ligeiro, I. Abreu, M. Carmo-Fonseca, and J.C. Branco, "Polymorphism at position -308 of the tumour necrosis factor alpha gene and rheumatoid arthritis pharmacogenetics," Ann. Rheum. Dis., vol. 64, pp. 793-794, 2005.
Y. M. Mosaad, A. Abdelsalam, and S. R. El-bassiony, "Association of tumour necrosis factor-alpha -308 G⁄A promoter polymorphism with susceptibility and disease profile of rheumatoid arthritis," International Journal of Immunogenetics, vol. 38, pp. 427–433, 2011.
K. M. Moukhtar, A. M. Ghoneim, N. El-Mashad, E. M. Hammad, and O Abu Samak, "Investigation of the genetic polymorphism of interleukin-10 gene in rheumatoid arthritis patients in Egypt," World Journal of Medical Sciences, vol. 10, pp. 319-325, 2014.
S. Jimenez-Morales, R. Velàzquez-Cruz, J. Ramırez-Bello, E. Bonilla-Gonzalez, S. Romero-Hidalgo, G. Escamilla-Guerrero, F. Cuevas, F. Espinosa-Rosales, N. E. Martínez-Aguilar, J. Gómez-Vera, V. Baca, and L Orozco, "Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population," Human Immunology, vol. 70, pp. 251-256, 2009.
M. M. Elahi, K. Asotra, B. M. Matata, and S. S. Mastana, "Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease," Biochimica et Biophysica Acta, vol. 1792, pp. 163-172, 2009.
A. Barton, H. Platt, F. Salway, D. Symmons, E. Barrett, M. Bukhari, M. Lunt, E. Zeggini, S. Eyre, A. Hinks, D. Tellam, B. Brintnell, W. Ollier, J. Worthington, and A. Silman, "Polymorphisms in the tumour necrosis factor gene are not associated with severity of inflammatory polyarthritis," Ann. Rheum. Dis., vol. 63, pp. 280–284, 2004.
N. Seki, S. Kamizono, A. Yamada, T. Higuchi, H. Matsumoto, F. Niiya, A. Kimura, K. Tsuchiya, R. Suzuki, Y. Date, T. Tomita, K. Itoh, and T. Ochi, "Polymorphisms in the 59-flanking region of tumor necrosis factor-alpha gene in patients with rheumatoid arthritis," Tissue Antigens, vol. 54, pp. 194–7, 1999.
J. Vinasco, Y. Beraun, A. Nieto, A. Fraile, L. Mataran, E. Pareja, and J. Martín, "Polymorphism at the TNF loci in rheumatoid arthritis," Tissue Antigens, vol. 49, pp. 74–8, 1997.
J. H. Yen, C. J. Chen, W. C. Tsai, C. H. Lin, T. T Ou, C. C. Wu, and H. W. Liu, "Tumor necrosis factor promoter polymorphisms in patients with rheumatoid arthritis in Taiwan," J. Rheumatol., vol. 28, pp. 1788–92, 2001.
B. M. Brinkman, T. W. Huizinga, S. S. Kurban, E. A. van der Velde, G. M. Schreuder, J. M. Hazes, F. C. Breedveld, and C. L. Verweij, "Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease?," Br. J. Rheumatol., vol. 36, pp. 516–21, 1997.
J. K. Lacki, R. Moser, I. Korczowska, S. Mackiewicz, and W. Muller, "TNF-alpha gene polymorphism does not affect the clinical and radiological outcome of rheumatoid arthritis," Rheumatol. Int., vol. 19, pp. 137–40, 2000.
M. Field, G. Gallagher, J. Eskdale, F. McGarry, S. D. Richards, R. Munro, H. H. Oh, and C Campbell, "Tumor necrosis factor locus polymorphisms in rheumatoid arthritis," Tissue Antigens, vol. 50, pp. 303–7, 1997.
A. S. Low, M. A. Gonzalez-Gay, M. Akil, R.S. Amos, D. E. Bax, C. Cannings, A. Hajeer, S. H. Till, J. Winfiel, W. E. Ollier, and A. G. Wilson, "TNF +489 polymorphism does not contribute to susceptibility to rheumatoid arthritis," Clin. Exp. Rheumatol., vol. 20, pp. 829–32, 2002.
M. V van Krugten, T. W. Huizinga, E. L. Kaijzel, E. Zanelli, K. W. Drossaers-Bakker, L. P. van de Linde, J. M. Hazes, A. H. Zwinderman, F. C. Breedveld, and C. L. Verweij, "Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis," Genes Immun., vol. 1, pp. 91–6, 1999.
F. Waldron-Lynch, C. Adams, C. Amos, D. K. Zhu, M. F. McDermott, F. Shanahan, M. G. Molloy, and F. O'Gara, "Tumour necrosis factor alpha promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immuno genetically defined multiplex RA families," Genes, vol. 2, pp. 82–7, 2001.
S. Ozen, M. Alikasifoglu, A. Bakkaloglu, A. Duzova, K. Jarosova, D. Nemcova, N. Besbas, J. Vencovsky, and E. Tuncbilek, "Tumor necrosis factor alpha G-A -238 and G-A -308 polymorphism in Juvenile idiopathic arthritis," Rheumatology, vol. 41, pp. 223-227, 2002.
Y. Tsunemi, A. Nishibu, H. Saeki, N. Oyama, K. Nakamura, M. Kishimoto, H. Mitsui, Y. Tada, H. Torii, M. Komine, A. Asahina, F. Kaneko, and K. Tamaki, "Lack of association between the promoter polymorphisms at positions -308 and -238 of the tumor necrosis factor alpha gene and psoriasis vulgaris in Japanese patients," Dermatology, vol. 207, pp. 371-4, 2003.
C. Epplen, H. Rumpf, E. Albert, P. Haas, H. Truckenbrodt, and J. T. Epplen, "Immunoprinting excludes many potential susceptibility genes as predisposing to early onset pauciarticular juvenile chronic arthritis except HLA Class II and TNF," Eur. J Immunogent., vol. 22, pp. 311-322, 1995.
A. I. Arias, B. Giles, T. H. Eiermann, W. Sterry, and J. P. Pandey, "Tumor necrosis factor- alpha gene polymorphism in psoriasis," Exp. Clin. Immunogenet, vol. 14, pp. 118-22, 1997.
H. Schmeling, U. Wagner, A. Peterson, and G. Horneff, "Tumor necrosis factor alpha promoter polymorphisms in patients with juvenile idiopathic arthritis," Clinical and Experimental Rheumatology, vol. 24, pp. 103-108, 2006.
T. Hohler, S. Grossmann, B. Stradmann-Bellinghausen, W. Kaluza, E. Reuss, K. deVlam, E. Veys, and E. Märker-Hermann, "Differential association of polymorphisms in the TNFa region with psoriatic arthritis but not psoriasis," Ann. Rheum. Dis., vol. 61, pp. 213–18, 2002.
T. Hohler, A. Kruger, P. M. Schneider, R. E. Schopf, J. Knop, C. Rittner, K. H. Meyerzum Büschenfelde, and E. Märker-Hermann, "A TNF- alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis," J. Invest. Dermatol., vol. 109, pp. 562–5, 1997.
A. M. Al-Heresh, J. Proctor, S. M. Jones, J. Dixey, B. Cox, K. Welsh, and N. McHugh, "Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis," Rheumatology, vol. 41, pp. 525–30, 2002.
J. Balding, D. Kane, W. Livingstone, L. Mynett-Johnson, B. Bresnihan, O. Smith, and O. FitzGerald, "Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity," Arthritis Rheum., vol. 48, pp. 1408–13, 2003.
S. Gonzalez, C. Brautbar, J. Martinez-Borra, A. Lopez-Vazquez, R. Segal, M. A. Blanco-Gelaz, C. D. Enk, C. Safriman, and C. López-Larrea, "Polymorphism in MICA rather than HLA-B/C genes is associated with psoriatic arthritis in the Jewish population," Hum. Immunol., vol. 62, pp. 632–8, 2001.
S. Gonzalez, J. Martinez-Borra, A. Lopez-Vazquez, S. Garcia-Fernandez, J. C. Torre-Alonso, and C. Lopez-Larrea, "MICA rather than MICB, TNFa, or HLA-DRB1 is associated with susceptibility to psoriatic arthritis," J. Rheumatol. Vol. 29, pp. 973–8, 2002.
P. Rahman, F. Siannis, C. Butt, V. Farewell, L. Peddle, F. Pellett, and D. Gladman, "TNFa polymorphisms and risk of psoriatic arthritis," Ann. Rheum. Dis., vol. 65, pp. 919–923, 2006.
M. Fabris, P. E. Di, A. D'Elia, G. Damante, L. Sinigaglia, and G. Ferraccioli, "Tumor necrosis factor-α gene polymorphism in severe and mild-moderate rheumatoid arthritis," J. Rheumatol., vol. 29, pp. 29-33, 2002.
E. L. Kaijzel, M. V. van Krugten, B. M. Brinkman, T. W. Huizinga, T. van der Straaten, J. M. Hazes, H. W. Ziegler-Heitbrock, S. A. Nedospasov, F. C. Breedveld, and C. L. Verweij, "Functional analysis of a human tumor necrosis factor alpha (TNF-alpha) promoter polymorphism related to joint damage in rheumatoid arthritis," Mol. Med., vol. 4, pp. 724–33, 1998.
T. W. J. Huizinga, R. G. J. Westendorp, E. L. E. M. Bollen, V. Keijsers, B. M. Brinkman, J. A. Langermans, F. C. Breedveld, C. L. Verweij, L. van de Gaer, L. Dams, J. B. Crusius, A. García-Gonzalez, B. W. van Oosten, C. H. Polman, and A. S. Peña, "TNF-a polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients," J. Neuro. immunol., vol. 72, pp. 149-153, 1997.
F. Pociot, A. D'Alfonso, S. Compasso, R. Scorza, and P. M. Richiardi, "Functional analysis of a new polymorphism in the human TNF alpha gene promoter," Scand J. Immunol., vol. 42, pp. 501-504, 1995.
S. D'Alfonso, and P. M. Richiardi, "An intragenic polymorphism in the human tumor necrosis factor alpha (TNFA) chain-encoding gene," ImmunoGenetics, vol. 44, pp. 321-322, 1996.
D. J. Conway, M. J. Holland, R. L. Bailey, A. E. Campbell, O. S. Mahdi, R. Jennings, E. Mbena, and D. C. Mabey, "Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-a) gene promoter and with elevated TNF-a levels in tear fluid," Infection Immunity, vol. 65, pp. 1003-1006, 1997.
J. Grove, A. K. Daly, M. F. Bassendine, and C. P. Day, "Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis," Hepatology, vol. 26, pp. 143-146, 1997.
W. H. Jang, Y. I. Yang, S. S. Yea, Y. J. Lee, J. H. Chun, H. I. Kim, M. S. Kim, and K. H. Paik, "The -238 tumor necrosis factor-alpha promoter polymorphism is associated with decreased susceptibility to cancers," Cancer Lett., vol. 166, pp. 41-46, 2001.
T. Hohler, A. Kruger, G. Gerken, P. M. Schneider, K. H. Meyerzum Büschenfelde, and C Rittner, "Tumor necrosis factor alpha promoter polymorphism at position -238 is associated with chronic active hepatitis C infection," J. Med. Virol., vol. 54, pp. 173-7, 1998.
C. Y. Dai, W. L. Chuang, L. P. Lee, S. C. Chen, N. J. Hou, Z. Y. Lin, M. Y. Hsieh, M. Y. Hsieh, L. Y. Wang, W. Y. Chang, and M. L. Yu, "Associations of tumour necrosis factor alpha promoter polymorphisms at position -308 and -238 with clinical characteristics of chronic hepatitis C," J. Viral Hepat., vol. 13, pp. 770-4, 2006.
J. C. Knight, I. Udalova, A. V. Hill, B. M. Greenwood, N. Peshu, K. Marsh, and D. Kwiatkowski, "A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria," Nat. Genet., vol. 22, pp. 145–150, 1999.
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