Acta Medica Iranica 2018. 56(7):429-433.

The Pattern of Methylation and Polymorphism in Interleukin-6 Promoter Gene Are Related to the Development of Rheumatoid Arthritis?
Isaura Isabelle Fonseca Gomes-Silva, Eliezer Rushansky, Francisco Geraldo Carvalho-Neto, Amanda Virginia Batista Vieira, Maria Helena Queiroz de Araujo Mariano, Paulo Roberto Eleutério de Souza, Martín Alejandro Montes, Maria Mascena Diniz Maia


Rheumatoid Arthritis (RA) is a complex disease with higher level of IL-6. In order to elucidate the alterations related to IL-6 gene in RA, we evaluated the -174 G/C IL-6 gene polymorphism and methylation pattern of its promoter. A total of 120 RA patients and 120 healthy controls were recruited for polymorphism analysis, and 30 individuals of both groups were randomly selected for methylation analysis. The IL-6 gene polymorphism was analyzed by PCR-RFLP and methylation pattern was analyzed by MSP-PCR. Regarding IL-6 gene polymorphism, no significant difference was found between RA patients and controls (P>0.05). For DNA, two CpG regions of IL-6 promoter gene was analyzed. The first region (−1069, −1061, −1057 and −1001 CpG) did not show significant differences, whereas the second region (−628, −610, −574 and −491 CpG) showed a significant hypermethylated status (P=0.0004) in RA patients as compared with controls.These results, suggest a possible relationship between methylation pattern and the susceptibility to RA in our studied population.


Cytokine; Inflammation; Epigenetics; MSP-PCR; Single nucleotide polymorphism

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Trenkmann M, Brock M, Ospelt C, et al. Epigenetics in Rheumatoid Arthritis. Clin. Rev. Allergy Immunol 2010; 39(1): 10–19.

Trajkov D, Mishevska-Perchinkova S, Karadzova-Stojanoska A, et al. Association of 22 cytokine gene polymorphisms with rheumatoid arthritis in population of ethnic Macedonians. Clin Rheumatol 2009; 28(11): 1291–1300.

Gierut A, Perlman H, Pope RM. Innate Immunity and Rheumatoid Arthritis. Rheum. Dis Clin N Am 2010; 36(2): 271–296.

Yoshida Y, Tanaka T. Interleukin 6 and Rheumatoid Arthritis. Bio Med Res Int 2014; 1–12.

Le Goff B, Blanchard F, Berthelot JM, et al. Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis. Joint Bone Spine 2010; 77(3): 201–205.

Solus JF, Chung CP, Oeser A, et al. Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis. Clin Rheumatol 2015; 34(8):1375–1382.

Li X, Chai W, Ni M, et al. The Effects of Gene Polymorphisms in Interleukin-4 and Interleukin-6 on the Susceptibility of Rheumatoid Arthritis in a Chinese Population. Bio Med Res 2014; 1–5.

Angelo HD, Gomes Silva IIF, Oliveira RDR, et al. Interleukin-18, interleukin-12B and interferon-γ gene polymorphisms in Brazilian patients with rheumatoid arthritis: a pilot study: IL-18, IL-12B and IFN-γ gene polymorphisms and rheumatoid arthritis. Tissue Antigens 2015; 86(4): 276–278.

Bennermo M. Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases? Clin Chem 2004; 50(11): 2136–2140.

Col-Araz N, Pehlivan S, Baspinar O. et al. Role of cytokine gene (IFN-γ, TNF-α, TGF-β1, IL-6, and IL-10) polymorphisms in pathogenesis of acute rheumatic fever in Turkish children. Eur J Pediatr 2012; 171(7):1103–1108.

Pola E, Papaleo P, Pola R, et al. Interleukin-6 gene polymorphism and risk of osteoarthritis of the hip: a case–control study. Osteoarthritis Cartilage 2005; 13(11):1025–1028.

Nile CJ, Read RC, Akil M, et al. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 2008; 58(9): 2686–2693.

Stefani FA, Viana MB, Dupim AC, et al. Expression, polymorphism and methylation pattern of interleukin-6 in periodontal tissues. Immunobiology 2013; 218(7): 1012–1017.

Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31(3):315–24.

Pappas JJ, Toulouse A, Bradley WEC. The bisulfite genomic sequencing protocol. Adv Lung Cancer 2013; 2(1): 21–25.

Asano NM, Angelo HD, da Silva HA, et al. Interleukin-6 promoter polymorphisms −174 G/C in Brazilian patients with systemic lupus erythematosus. Hum Immunol 2013; 74(9): 1153–1156.

Team RC, R. A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2013. ((Accessed March 4, 2017, at http. www. R-project. org).

Zavaleta-Muñiz SA, Martín-Márquez BT, Gonzalez-Lopez L, et al. Patients The −174G/C and −572G/C Interleukin 6 Promoter Gene Polymorphisms in Mexican with Rheumatoid Arthritis: A Case-Control Study. Clin Dev Immunol 2013;2013: 1–5.

Palomino-Morales R, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, et al. Interleukin-6 gene-174 promoter polymorphism is associated with endothelial dysfunction but not with disease susceptibility in patients with rheumatoid arthritis. Clin Exp Rheumatol 2009; 27(6): 964–970.

Arman A, Coker A, Sarioz O, et al. Lack of association between IL-6 gene polymorphisms and rheumatoid arthritis in Turkish population. Rheumatol Int 2012; 32(7): 2199–2201.

Amr K, El-Awady R, Raslan H. Assessment of the −174G/C (rs1800795) and −572G/C (rs1800796) Interleukin 6 Gene Polymorphisms in Egyptian Patients with Rheumatoid Arthritis. Open Access Maced J Med Sci 2016; 4(4): 574-577.

Dar SA, Haque S, Mandal RK, et al. Interleukin-6-174G/C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis. Autoimmunity 2016; 1–12.

Ishida K, Kobayashi T, Ito S, et al. Interleukin-6 Gene Promoter Methylation in Rheumatoid Arthritis and Chronic Periodontitis. J Periodontol 2012; 83(7): 917–925.

Kojima A, Kobayashi T, Ito S, et al. Tumor necrosis factor-alpha gene promoter methylation in Japanese adults with chronic periodontitis and rheumatoid arthritis. J Periodontal Res 2016; 51(3): 350–358.

Na YK, Hong HS, Lee WK, et al. Increased Methylation of Interleukin 6 Gene Is Associated with Obesity in Korean Women. Mol Cells 2015; 38(5): 452–456


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