The Correlation Between Plasma Levels of Vitamin D and Epigenetic Alterations of Treg-Specific Demethylated Region (TSDR) in Rheumatoid Arthritis Patients
Rheumatoid arthritis (RA) is the most common autoimmune inflammatory disease of joints among adults. Regulatory T cells (Treg) control immune responses in this illness. Through the expression of FoxP3, a Treg transcription factor, Vitamin D keeps autoimmune diseases in check. Yet, the molecular mechanism of FoxP3 expression by vitamin D is not well-inspected. It may influence FoxP3 expression via epigenetic changes. This study aimed to investigate the correlation between plasma levels of vitamin D and the demethylation of the TSDR region in Foxp3 promoter in patients with RA. Twenty untreated RA patients and 41 healthy controls participated in this study. Plasma levels of 25-OH vitamin D were measured by competitive ELISA method. The demethylation of TSDR regions in Foxp3 gene was also assessed using the quantitative Methylation Specific PCR (qMSP) method. The demethylation of TSDR region was significantly lower in RA patients compared with healthy controls (P=0.006). Vitamin D plasma levels were significantly higher in RA patients rather than healthy people (P=0.034). There was no statistically significant correlation between vitamin D plasma levels and demethylation of TSDR region. As expected, epigenetic alternation showed considerable difference between RA patients and healthy controls, but about vitamin D correlation with methylation modification, more studies are needed.
. Fessler J, Felber A, Duftner C, Dejaco C (2013) Therapeutic potential of regulatory T cells in autoimmune disorders. BioDrugs 27:281-291.
. Haque M, Fino K, Lei F, Xiong X, Song J (2014) Utilizing regulatory T cells against rheumatoid arthritis. Front Oncol 4:209.
. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko S-A, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68.
. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20.
. Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, Hamann A, Wagner H, Huehn J, Sparwasser T (2007) Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 204:57-63.
. Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191.
. Brennan FM, McInnes IB (2008) Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537-3545.
. Huisman AM, White KP, Algra A, Harth M, Vieth R, Jacobs J, Bijlsma J, Bell DA (2001) Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia. J Rheumatol 28:2535-2539.
. Kerr GS, Sabahi I, Richards JS, Caplan L, Cannon GW, Reimold A, Thiele GM, Johnson D, Mikuls TR (2011) Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 38:53-59.
. Haque U, Bartlett S (2010) Relationships among vitamin D, disease activity, pain and disability in rheumatoid arthritis. Clin Exp Rheumatol 28:745-747.
. Arnson Y, Amital H, Shoenfeld Y (2007) Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 66:1137-1142.
. Kang SW, Kim SH, Lee N, Lee W-W, Hwang K-A, Shin MS, Lee S-H, Kim W-U, Kang I (2012) 1, 25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol 188:5276-5282.
. Correale J, Ysrraelit MC, Gaitán MI (2009) Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 132:1146-1160.
. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes & development 16:6-21.
. Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38:1654-1663.
. Zafari P, Yari K, Mostafaei S, Iranshahi N, Assar S, Fekri A, Taghadosi M (2018) Analysis of Helios gene expression and Foxp3 TSDR methylation in the newly diagnosed Rheumatoid Arthritis patients. Immunol Invest 47:632-642.
. Doig CL, Singh PK, Dhiman VK, Thorne JL, Battaglia S, Sobolewski M, Maguire O, O’Neill LP, Turner BM, McCabe CJ (2012) Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns. Carcinogenesis 34:248-256.
. Barghi S, Amiri M, Hajipur H, Namaki S (2017) The Effect of Dietary Constituents on Regulation of Epigenetic Changes in Cancer. J Babol Univ Med Sci 19:63-71.
. Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215.
. Li L-C, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427-1431.
. Cottrell S, Jung K, Kristiansen G, Eltze E, Semjonow A, Ittmann M, Hartmann A, Stamey T, Haefliger C, Weiss G (2007) Discovery and validation of 3 novel DNA methylation markers of prostate cancer prognosis. J Urol 177:1753-1758.
. Sahebari M, Mirfeizi Z, Rezaieyazdi Z, Rafatpanah H, Goshyeshi L (2014) 25 (OH) vitamin D serum values and rheumatoid arthritis disease activity (DA S28 ESR). Caspian J Intern Med 5:148.
. Nielen MM, van Schaardenburg D, Lems WF, van de Stadt RJ, de Koning MH, Reesink HW, Habibuw MR, van der Horst‐Bruinsma IE, Twisk JW, Dijkmans BA (2006) Vitamin D deficiency does not increase the risk of rheumatoid arthritis: comment on the article by Merlino et al. Arthritis Rheumatol 54:3719-3720.
. Heidari B, Heidari P, Samari E, Ramzannia Jalali M (2014) Frequency of vitamin D deficiency in common musculo skeletal conditions. J Babol Univ Med Sci 16:7-15.
. Holick MF, Chen TC (2008) Vitamin D deficiency: a worldwide problem with health consequences–.Am J Clin Nutr 87:1080S-1086S.
. Elbassiony SR, Tawhid Z, Ahmad HS, Sabry A (2016) Serum 25-hydroxy vitamin D levels in Egyptian patients with rheumatoid arthritis: Association with disease activity, functional disability and radiological damage. Egypt Rheumatol 38:133-139.
. Sharma R, Saigal R, Goyal L, Mital P, Yadav R, Meena P, Agrawal A (2014) Estimation of vitamin D levels in rheumatoid arthritis patients and its correlation with the disease activity. J Assoc Physicians India 62:678-681.
. Gheita TA, Sayed S, Gheita HA, Kenawy SA (2016) Vitamin D status in rheumatoid arthritis patients: relation to clinical manifestations, disease activity, quality of life and fibromyalgia syndrome. Intern J Rheum Dis 19:294-299.
. Marinho A, Carvalho C, Boleixa D, Bettencourt A, Leal B, Guimarães J, Neves E, Oliveira JC, Almeida I, Farinha F (2017) Vitamin D supplementation effects on FoxP3 expression in T cells and FoxP3+/IL-17A ratio and clinical course in systemic lupus erythematosus patients: a study in a Portuguese cohort. Immunol Res 65:197-206.
. Florath I, Schottker B, Butterbach K, Bewerunge-Hudler M, Brenner H (2016) Epigenome-wide search for association of serum 25-hydroxyvitamin D concentration with leukocyte DNA methylation in a large cohort of older men. Epigenomics 8:487-499.
. Tapp HS, Commane DM, Bradburn DM, Arasaradnam R, Mathers JC, Johnson IT, Belshaw NJ (2013) Nutritional factors and gender influence age‐related DNA methylation in the human rectal mucosa. Aging cell 12:148-155.
. Rawson JB, Sun Z, Dicks E, Daftary D, Parfrey PS, Green RC, Gallinger S, McLaughlin JR, Wang PP, Knight JA (2012) Vitamin D intake is negatively associated with promoter methylation of the Wnt antagonist gene DKK1 in a large group of colorectal cancer patients. Nutr Cancer 64:919-928.
. Lopes N, Carvalho J, Duraes C, Sousa B, Gomes M, Costa JL, Oliveira C, Paredes J, Schmitt F (2012) 1Alpha, 25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation. Anticancer Res 32:249-257.
. Zhu H, Bhagatwala J, Huang Y, Pollock NK, Parikh S, Raed A, Gutin B, Harshfield GA, Dong Y (2016) Race/ethnicity-specific association of vitamin D and global DNA methylation: cross-sectional and interventional findings. PloS one 11:e0152849.
. Zafari P, Mostafaei S, Iranshahi N, Jalili C, Taghadosi M (2018) Relationship between vitamin D plasma level and Foxp3 gene expression among rheumatoid arthritis patients. Sci J Kurdistan Univ Med Sci 22:40-48.