Single Nucleotide Polymorphism rs2075876 in AIRE Gene Is a Strong Rheumatoid Arthritis Determinant
Abstract
Rheumatoid arthritis (RA) is a progressive and common autoimmune disease with multifactorial etiology. Several pieces of research show that genetic factors play a major role in the incidence of RA. Several genome-wide association studies (GWAS) have identified the autoimmune regulator (AIRE) gene as one of the candidate loci. This gene encodes a transcription factor, which is involved in the presentation of self-antigens and negative selection of self-reactive T-cells in the thymus. Studies have indicated that single nucleotide polymorphisms (SNPs) in the AIRE gene can change the gene expression and/or function. In the present study, we assessed the possible association between SNP rs2075876 (intronic variant) in the AIRE gene with RA risk in the Iranian population. A case-control study using 56 RA patients and 58 control subjects was undertaken to evaluate rs2075876 genotypes using real-time PCR high resolution melting method (HRM). Logistic regression analysis demonstrates that homozygous AA and heterozygous AG genotypes compared with GG genotype increase the risk of RA (AA vs GG; OR= 16.43; 95%CI [5.33-50.71] and AG vs GG; OR= 3.21; 95%CI [1.22-8.45]). Also, individuals with allele A were more frequently affected with RA than subjects with G allele (OR= 5.81; 95%CI [3.28-10.30]). Furthermore, in the patient group, we found a significant correlation between erythrocyte sedimentation rate and C-reactive protein concentration with rs2075876 polymorphism (P< 0.05). Our findings propose a substantial correlation between rs2075876 polymorphism and RA risk.
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2. Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res 2002;4:S265-72.
3. Dargham SR, Zahirovic S, Hammoudeh M, Al Emadi S, Masri BK, Halabi H, et al. Epidemiology and treatment patterns of rheumatoid arthritis in a large cohort of Arab patients. PloS one 2018;13:e0208240.
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5. van Vollenhoven RF. Sex differences in rheumatoid arthritis: more than meets the eye. BMC Med 2009;7:12.
6. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol 2014;35:347-69.
7. Ehtesham N, Zare Rafie M, Esmaeilzadeh E, Dehani M, Davar S, Mosallaei M, et al. Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus. Lupus. 2021: 6:09612033211014273.
8. Castro-Santos P, Díaz-Peña R. Genetics of rheumatoid arthritis: a new boost is needed in Latin American populations. Rev Bras Reumatol Engl Ed 2016;56:171-7.
9. Yarwood A, Huizinga TW, Worthington J. The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. Rheumatology (Oxford) 2016;55:199-209.
10. Jiang X, Frisell T, Askling J, Karlson EW, Klareskog L, Alfredsson L, et al. To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors? Arthritis Rheumatol 2015;67:352-62.
11. Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K. Genetics of rheumatoid arthritis: 2018 status. Ann Rheum Dis 2019;78:446-53.
12. Viatte S, Plant D, Raychaudhuri S. Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 2013;9:141-53.
13. Danila MI, Laufer VA, Reynolds RJ, Yan Q, Liu N, Gregersen PK, et al. Dense genotyping of immune-related regions identifies loci for rheumatoid arthritis risk and damage in African Americans. Mol Med 2017;23:177-87.
14. De Martino L, Capalbo D, Improda N, Lorello P, Ungaro C, Di Mase R, et al. Novel findings into AIRE genetics and functioning: clinical implications. Front Pediatr 2016;4:86.
15. Zhao B, Chang L, Fu H, Sun G, Yang W. The role of autoimmune regulator (AIRE) in peripheral tolerance. J Immunol Res 2018;2018:.3930750
16. Perniola R. Twenty years of AIRE. Front Immunol 2018;9:98.
17. Theofilopoulos AN, Bona CA. The molecular pathology of autoimmune diseases: CRC Press, 2002.
18. Zhu W, Hu Z, Liao X, Chen X, Zeng Z. AIRE Gene Mutation in Chinese APS-1 Patients. Adv Tech Biol Med 2017;5:2379-1764.1000235.
19. Xu YS, Jiang XJ, Chen JM. A single nucleotide polymorphism of AIRE gene located in the 21q22. 3 increases the risk of rheumatoid arthritis. Oncotarget 2017;8:71556-62.
20. Bérczi B, Gerencsér G, Farkas N, Hegyi P, Veres G, Bajor J, et al. Association between AIRE gene polymorphism and rheumatoid arthritis: a systematic review and meta-analysis of case-control studies. Sci Rep 2017;7:1-11.
21. Toraih EA, Ameen HM, Hussein MH, Youssef Elabd AA, Mohamed AM, Abdel-Gawad AR, et al. Association of Autoimmune Regulator Gene Rs2075876 Variant, but Not Gene Expression with Alopecia Areata in Males: A Case–control Study. Immunol Invest 2020;49:146-65.
22. Tazi‐Ahnini R, Cork M, Gawkrodger D, Birch M, Wengraf D, McDonagh A, et al. Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue Antigens 2002;60:489-95.
23. Ferrera F, Rizzi M, Sprecacenere B, Balestra P, Sessarego M, Di Carlo A, et al. AIRE gene polymorphisms in systemic sclerosis associated with autoimmune thyroiditis. Clin Immunol 2007;122:13-7.
24. Zhang X, Ding XJ, Wang Q, Yue YX, Xie Y, Hao HJ, et al. Rs3761389 polymorphism in autoimmune regulator (AIRE) gene is associated with susceptibility of myasthenia gravis in Chinese patients. J Clin Neurosci 2017;40:180-4.
25. Turunen JA, Wessman M, Forsblom C, Kilpikari R, Parkkonen M, Pöntynen N, et al. Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients. Immunogenetics 2006;58:331-8.
26. Montufar-Robles I, Robles-Garnica JC, Cadena-Sandoval D, Barbosa-Cobos RE, González-Castillo DD, Romero-Diaz J, et al. The AIRE Ser196Ser synonymous variant is a risk factor for systemic lupus erythematosus. Cell Immunol 2019;346:103986.
27. Tazi‐Ahnini R, McDonagh A, Wengraf D, Lovewell T, Vasilopoulos Y, Messenger A, et al. The autoimmune regulator gene (AIRE) is strongly associated with vitiligo. Br J Dermatol 2008;159:591-6.
28. Vogel A, Liermann H, Harms A, Strassburg CP, Manns MP, Obermayer-Straub P. Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1. Hepatology 2001;33:1047-52.
29. Conteduca G, Ferrera F, Pastorino L, Fenoglio D, Negrini S, Sormani M, et al. The role of AIRE polymorphisms in melanoma. Clin Immunol 2010;136:96-104.
30. Terao C, Yamada R, Ohmura K, Takahashi M, Kawaguchi T, Kochi Y, et al. The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population. Hum Mol Genet 2011;20:2680-5.
31. Feng Z-J, Zhang S-L, Wen H-F, Liang Y. Association of rs2075876 polymorphism of AIRE gene with rheumatoid arthritis risk. Hum Immunol 2015;76:281-5.
32. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.
33. Shao S, Li X-R, Cen H, Yin Z-S. Association of AIRE polymorphisms with genetic susceptibility to rheumatoid arthritis in a Chinese population. Inflammation 2014;37:495-9.
34. Li X, Li T, Chen M, Chai Y. Association of AIRE gene polymorphisms with susceptibility to rheumatoid arthritis among ethnic Han Chinese from Shaanxi. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2016;33:373-7.
35. García-Lozano J-R, Torres-Agrela B, Montes-Cano M-A, Ortiz-Fernández L, Conde-Jaldón M, Teruel M, et al. Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study. Arthritis Res Ther 2013;15:R11.
2. Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res 2002;4:S265-72.
3. Dargham SR, Zahirovic S, Hammoudeh M, Al Emadi S, Masri BK, Halabi H, et al. Epidemiology and treatment patterns of rheumatoid arthritis in a large cohort of Arab patients. PloS one 2018;13:e0208240.
4. Gabriel S, Crowson C. Epidemiology of Risk Factors for, and Possible Causes of Rheumatoid Arthritis. Up to Date 2018.
5. van Vollenhoven RF. Sex differences in rheumatoid arthritis: more than meets the eye. BMC Med 2009;7:12.
6. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol 2014;35:347-69.
7. Ehtesham N, Zare Rafie M, Esmaeilzadeh E, Dehani M, Davar S, Mosallaei M, et al. Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus. Lupus. 2021: 6:09612033211014273.
8. Castro-Santos P, Díaz-Peña R. Genetics of rheumatoid arthritis: a new boost is needed in Latin American populations. Rev Bras Reumatol Engl Ed 2016;56:171-7.
9. Yarwood A, Huizinga TW, Worthington J. The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. Rheumatology (Oxford) 2016;55:199-209.
10. Jiang X, Frisell T, Askling J, Karlson EW, Klareskog L, Alfredsson L, et al. To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors? Arthritis Rheumatol 2015;67:352-62.
11. Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K. Genetics of rheumatoid arthritis: 2018 status. Ann Rheum Dis 2019;78:446-53.
12. Viatte S, Plant D, Raychaudhuri S. Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 2013;9:141-53.
13. Danila MI, Laufer VA, Reynolds RJ, Yan Q, Liu N, Gregersen PK, et al. Dense genotyping of immune-related regions identifies loci for rheumatoid arthritis risk and damage in African Americans. Mol Med 2017;23:177-87.
14. De Martino L, Capalbo D, Improda N, Lorello P, Ungaro C, Di Mase R, et al. Novel findings into AIRE genetics and functioning: clinical implications. Front Pediatr 2016;4:86.
15. Zhao B, Chang L, Fu H, Sun G, Yang W. The role of autoimmune regulator (AIRE) in peripheral tolerance. J Immunol Res 2018;2018:.3930750
16. Perniola R. Twenty years of AIRE. Front Immunol 2018;9:98.
17. Theofilopoulos AN, Bona CA. The molecular pathology of autoimmune diseases: CRC Press, 2002.
18. Zhu W, Hu Z, Liao X, Chen X, Zeng Z. AIRE Gene Mutation in Chinese APS-1 Patients. Adv Tech Biol Med 2017;5:2379-1764.1000235.
19. Xu YS, Jiang XJ, Chen JM. A single nucleotide polymorphism of AIRE gene located in the 21q22. 3 increases the risk of rheumatoid arthritis. Oncotarget 2017;8:71556-62.
20. Bérczi B, Gerencsér G, Farkas N, Hegyi P, Veres G, Bajor J, et al. Association between AIRE gene polymorphism and rheumatoid arthritis: a systematic review and meta-analysis of case-control studies. Sci Rep 2017;7:1-11.
21. Toraih EA, Ameen HM, Hussein MH, Youssef Elabd AA, Mohamed AM, Abdel-Gawad AR, et al. Association of Autoimmune Regulator Gene Rs2075876 Variant, but Not Gene Expression with Alopecia Areata in Males: A Case–control Study. Immunol Invest 2020;49:146-65.
22. Tazi‐Ahnini R, Cork M, Gawkrodger D, Birch M, Wengraf D, McDonagh A, et al. Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue Antigens 2002;60:489-95.
23. Ferrera F, Rizzi M, Sprecacenere B, Balestra P, Sessarego M, Di Carlo A, et al. AIRE gene polymorphisms in systemic sclerosis associated with autoimmune thyroiditis. Clin Immunol 2007;122:13-7.
24. Zhang X, Ding XJ, Wang Q, Yue YX, Xie Y, Hao HJ, et al. Rs3761389 polymorphism in autoimmune regulator (AIRE) gene is associated with susceptibility of myasthenia gravis in Chinese patients. J Clin Neurosci 2017;40:180-4.
25. Turunen JA, Wessman M, Forsblom C, Kilpikari R, Parkkonen M, Pöntynen N, et al. Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients. Immunogenetics 2006;58:331-8.
26. Montufar-Robles I, Robles-Garnica JC, Cadena-Sandoval D, Barbosa-Cobos RE, González-Castillo DD, Romero-Diaz J, et al. The AIRE Ser196Ser synonymous variant is a risk factor for systemic lupus erythematosus. Cell Immunol 2019;346:103986.
27. Tazi‐Ahnini R, McDonagh A, Wengraf D, Lovewell T, Vasilopoulos Y, Messenger A, et al. The autoimmune regulator gene (AIRE) is strongly associated with vitiligo. Br J Dermatol 2008;159:591-6.
28. Vogel A, Liermann H, Harms A, Strassburg CP, Manns MP, Obermayer-Straub P. Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1. Hepatology 2001;33:1047-52.
29. Conteduca G, Ferrera F, Pastorino L, Fenoglio D, Negrini S, Sormani M, et al. The role of AIRE polymorphisms in melanoma. Clin Immunol 2010;136:96-104.
30. Terao C, Yamada R, Ohmura K, Takahashi M, Kawaguchi T, Kochi Y, et al. The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population. Hum Mol Genet 2011;20:2680-5.
31. Feng Z-J, Zhang S-L, Wen H-F, Liang Y. Association of rs2075876 polymorphism of AIRE gene with rheumatoid arthritis risk. Hum Immunol 2015;76:281-5.
32. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.
33. Shao S, Li X-R, Cen H, Yin Z-S. Association of AIRE polymorphisms with genetic susceptibility to rheumatoid arthritis in a Chinese population. Inflammation 2014;37:495-9.
34. Li X, Li T, Chen M, Chai Y. Association of AIRE gene polymorphisms with susceptibility to rheumatoid arthritis among ethnic Han Chinese from Shaanxi. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2016;33:373-7.
35. García-Lozano J-R, Torres-Agrela B, Montes-Cano M-A, Ortiz-Fernández L, Conde-Jaldón M, Teruel M, et al. Association of the AIRE gene with susceptibility to rheumatoid arthritis in a European population: a case control study. Arthritis Res Ther 2013;15:R11.
| Files | ||
| Issue | Vol 59, No 5 (2021) | |
| Section | Articles | |
| DOI | https://doi.org/10.18502/acta.v59i5.6660 | |
| Keywords | ||
| Rheumatoid arthritis AIRE gene Single-nucleotide polymorphism Autoimmune disorder | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Salesi M, Noormohamadi E, Pakzad B, Yousefisadr F, Salehi R. Single Nucleotide Polymorphism rs2075876 in AIRE Gene Is a Strong Rheumatoid Arthritis Determinant. Acta Med Iran. 2021;59(5):259-264.
