eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 15
Basic research

Lack of association of –863C/A (rs1800630) polymorphism of tumor necrosis factor-α gene with rheumatoid arthritis

Tayyaba Sadaf, Peter John, Attya Bhatti, Javaid M. Malik

Arch Med Sci 2019; 15, 2: 531–536
Online publish date: 2018/07/05
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
Multifunctional pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) has been implicated in a variety of inflammatory diseases including rheumatoid arthritis (RA). TNF-α polymorphisms are mostly located in its promoter region and play a significant role in disease susceptibility and severity. We therefore sought to investigate TNFA –863C/A (rs1800630) polymorphism association with RA activity in our Pakistani study group.

Material and methods
A total of 268 human subjects were enrolled. Among them, 134 were RA patients and 134 were controls. In this study the physical parameters of RA patients were collected, and the disease activity was measured by DAS28. The genotypes were determined following the allele-specific PCR along with the pre-requisite internal amplification controls. Subsequently, data were analyzed statistically for any significant association including χ2/Fisher’s exact test using GraphPad prism 6 software.

We found that the TNF-α –863 C/A (rs1800630) variant was not differentially segregated between cases and controls in either genotype frequency, with χ2 of 2.771 and a p-value of 0.2502, or allele frequency, with χ2 of 2.741 and a p-value of 0.0978, with an odds ratio (95% CI) of 0.7490 (0.5317–1.055).

The lack of positive association of TNF-α –863(rs1800630) polymorphism in our study group implies that TNF-α –863 polymorphism is not a susceptible marker to RA and cannot serve as a genetic factor for screening RA patients in Pakistan. There might be other factors that may influence disease susceptibility. However, further investigations on additional larger and multi-regional population samples are required to determine the consequences of genetic variations for disease prognosis.


rheumatoid arthritis, polymorphism, tumor necrosis factor-alpha, association study

Cross M, Smith E, Hoy D, et al. The global burden of rheumatoid arthritis: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014; 73: 1316-22.
Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 2005; 4: 130-6.
Farooqi A, Gibson T. Prevalence of the major rheumatic disorders in the adult population of north Pakistan. Br J Rheumatol 1998; 37: 491-5.
Klareskog L, Padyukov L, Rönnelid J, Alfredsson L. Genes, environment and immunity in the development of rheumatoid arthritis. Curr Opin Immunol 2006; 18: 650-5.
Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004; 75: 330-7.
Pawlik A, Herczyńska M, Kurzawski M, et al. IL-1beta, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis patients with leflunomide. Pharmacol Rep 2009; 61: 281-7.
Ota M, Katsuyama Y, Kimura A, et al. A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region. Genomics 2001; 71: 263-70.
Zanelli E, Jones G, Pascual M, et al. The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci. Hum Immunol 2001; 62: 75-84.
Jawaheer D, Li W, Graham RR, et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 2002; 71: 585-94.
Fonseca JE, Cavaleiro J, Teles J, et al. Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequencing of the tumor necrosis factor-alpha gene promoter. Arthritis Res Ther 2007; 9: R37.
Bayley JP, Ottenhoff TH, Verweij CL. Is there a future for TNF promoter polymorphisms? Genes Immun 2004; 5: 315-29.
Udalova IA, Richardson A, Denys A, et al. Functional consequences of a polymorphism affecting NF-kappaB p50-p50 binding to the TNF promoter region. Mol Cell Biol 2000; 20: 9113-9.
Skoog T, van’t Hooft FM, Kallin B, et al. A common functional polymorphism (C → A substitution at position− 863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet 1999; 8: 1443-9.
Udalova IA, Richardson A, Ackerman H, Wordsworth P, Kwiatkowski D. Association of accelerated erosive rheumatoid arthritis with a polymorphism that alters NF-kappaB binding to the TNF promoter region. Rheumatology (Oxford) 2002; 41: 830-1.
Gambhir D, Lawrence A, Aggarwal A, Misra R, Mandal SK, Naik S. Association of tumor necrosis factor alpha and IL-10 promoter polymorphisms with rheumatoid arthritis in North Indian population. Rheumatol Int 2010; 30: 1211-7.
John P, Bhatti A, ul Ain N, Iqbal T, Sadaf T, Malik JM. Case-control study of vitamin D receptor gene polymorphism in Pakistani rheumatoid arthritis patients. Rev Bras Reumatol Engl Ed 2017; 57: 633-6.
Sadaf T, John P, Bhatti A, et al. Lack of tumor necrosis factor alpha gene polymorphism-857c/t (rs1799724) association in Pakistani rheumatoid arthritis patients. Int J Rheum Dis 2016; 19: 1119-25.
Kibbe WA. OligoCalc: an online oligonucleotide properties calculator. Nucleic Acids Res 2007; 35 (Suppl 2): W43-6.
MacGregor AJ, Snieder H, Rigby AS, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000; 43: 30-7.
Jawaheer D, Seldin MF, Amos CI, et al. Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. Arthritis Rheum 2003; 48: 906-16.
MacKay K, Eyre S, Myerscough A, et al. Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum 2002; 46: 632-9.
Fisher SA, Lanchbury JS, Lewis CM. Meta-analysis of four rheumatoid arthritis genome-wide linkage studies: confirmation of a susceptibility locus on chromosome 16. Arthritis Rheum 2003; 48: 1200-6.
Vries ND, Tijssen H, Riel PL, Putte LB. Reshaping the shared epitope hypothesis: HLA-associated risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67-74 of the HLA-DRB1 molecule. Arthritis Rheum 2002; 46: 921-8.
Yen JH, Chen CJ, Tsai WC, et al. Tumor necrosis factor promoter polymorphisms in patients with rheumatoid arthritis in Taiwan. J Rheumatol 2001; 28: 1788-92.
Raina P, Matharoo K, Kumar A, Sarangal P, Sharma R, Bhanwer AJS. Association of tumor necrosis factor-alpha –308 G>A polymorphism with rheumatoid arthritis in two north Indian cohorts. Arch Rheumatol 2014; 29: 241-9.
Fonseca JE, Cavaleiro J, Teles J, et al. Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequencing of the tumor necrosis factor-alpha gene promoter. Arthritis Res Ther 2007; 9: R37.
Kirkham BW, Lassere MN, Edmonds JP, et al. Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 2006; 54: 1122-31.
Richardson A, Sisay-Joof F, Ackerman H, et al. Nucleotide diversity of the TNF gene region in an African village. Genes Immun 2001; 2: 343-8.
Bayley JP, Ottenhoff TH, Verweij CL. Is there a future for TNF promoter polymorphisms? Genes Immun 2004; 5: 315-29.
Lis K, Kuzawińska O, Bałkowiec-Iskra E. Tumor necrosis factor inhibitors – state of knowledge. Arch Med Sci 2014; 10: 1175-85.
Zheng X, Zhou J, Xia Y. The role of TNF-alpha in regulating ketamine-induced hippocampal neurotoxicity. Arch Med Sci 2015; 11: 1296-302.
El-Tahan RR, Ghoneim AM, El-Mashad N. TNF-alpha gene polymorphisms and expression. Springerplus 2016; 5: 1508.
De Vries N, Tak PP. The response to anti-TNF-alpha treatment: gene regulation at the bedside. Rheumatology (Oxford) 2005; 44: 705-7.
Fonseca JE, Carvalho T, Cruz M, et al. Polymorphism at position –308 of the tumour necrosis factor α gene and rheumatoid arthritis pharmacogenetics. Ann Rheum Dis 2005; 64: 793-4.
Sashio H, Tamura K, Ito R, et al. Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn’s disease, respectively. Immunogenetics 2002; 53: 1020-7.
Li H, Groop L, Nilsson A, Weng J, Tuomi T. A combination of human leukocyte antigen DQB1* 02 and the tumor necrosis factor alpha promoter G308A polymorphism predisposes to an insulin-deficient phenotype in patients with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 2767-74.
Correa PA, Gomez LM, Cadena J, Anaya JM. Autoimmunity and tuberculosis. Opposite association with TNF polymorphism. J Rheumatol 2005; 32: 219-24.
Höhler T, Grossmann S, Stradmann-Bellinghausen B, et al. Differential association of polymorphisms in the TNFalpha region with psoriatic arthritis but not psoriasis. Ann Rheum Dis 2002; 61: 213-8.
Balding J, Kane D, Livingstone W, et al. Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity. Arthritis Rheum 2003; 48: 1408-13.
Rahman P, Siannis F, Butt C, et al. TNFalpha polymorphisms and risk of psoriatic arthritis. Ann Rheum Dis 2006; 65: 919-23.
Murdaca G, Gulli R, Spanò F, et al. TNF-alpha gene polymorphisms: association with disease susceptibility and response to anti-TNF-alpha treatment in psoriatic arthritis. J Invest Dermatol 2014; 134: 2503-9.
Jiménez-Morales S, Velázquez-Cruz R, Ramírez-Bello J, et al. Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population. Hum Immunol 2009; 70: 251-6.
Modesto C, Patiño-García A, Sotillo-Piñeiro E, et al. TNF- alpha promoter gene polymorphisms in Spanish children with persistent oligoarticular and systemic-onset juvenile idiopathic arthritis. Scand J Rheumatol 2005; 34: 451-4.
González S, Rodrigo L, Martínez-Borra J, et al. TNF-alpha -308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn’s patients with fistulizing disease. Am J Gastroenterol 2003; 98: 1101-6.
Uglialoro AM, Turbay D, Pesavento PA, et al. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens 1998; 52: 359-67.
Seki N, Kamizono S, Yamada A, et al. Polymorphisms in the 5′-flanking region of tumor necrosis factor-alpha gene in patients with rheumatoid arthritis. Tissue Antigens 1999; 54: 194-7.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe