Polymorphism rs10499194 of the TNFA1P3 gene is not associated with a predisposition to ankylosing spondylitis in the Russian cohort of patients

Background. Recently, numerous studies have shown that TNFAIP3 gene polymorphisms have been associated with susceptibility to certain autoimmune inflammatory diseases, including systemic lupus erythematosus, scleroderma, rheumatoid arthritis and psoriasis. However, the results of studies devoted to the study of associations between TNFAIP3 gene polymorphisms and the risk of ankylosing spondylitis (AS) are ambiguous and few.
The aim of the study was to study the possible association of hs10499194 polymorphism of the TNFAIP3 gene with a predisposition to AS and its clinical phenotypes.
Material and methods. The rs10499194 S/T polymorphism of the TNFA1P3 gene was studied in two hundred patients with AS (130 men and 70 women). All patients were diagnosed with AS, according to the modified New York criteria, 1984 and high activity of the disease. Demographic and clinical-serological characteristics were studied in all patients. The average age of patients was 39.4±12.6 years; the average duration of the disease was 15.0±10.6 years. Out of 200 patients, 175 (87.5%) were seropositive for HLA-B27 antigen. Extra axial arthritis was detected in 125 (62.5%) patients, 148 (74.0%) had enthesitis, 137 (68.5%) had coxitis. The polymorphism rs10499194 of the TNFAIP3 gene was studied using an allelespecific polymerase chain reaction in real time (PCR-RV) using the Synthol kit.
Results. The analysis of the frequencies of genotypes and alleles did not show significant differences with the control group. Stratification by sex, age, and clinical manifestations showed an association of the CT genotype with an increased risk of AS among men (OR=2.24; p=0.010), the TT genotype and the T allele with a high risk of predisposition to the development of extra axillary peripheral arthritis (OR=3.94; p=0.019 and OR=1.64; p=0.027 respectively). The BASDAI index was statistically significantly higher in carriers of the TT genotype compared to the CT genotype (p=0.002).
Conclusion. The present study confirmed the association of the genetic polymorphism rs10499194 of the TNFAIP3 gene with AS. Stratification by gender and clinical manifestations showed an association of the CT genotype with an increased risk of AS among men, the TT genotype and the T allele with a high risk of predisposition to the development of extra axillary peripheral arthritis and a high BASDAI index in carriers of the TT genotype.

1. Erdes ShF. Spondyloarthritis: Evolution of a concept. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2014;52(5):474-476 (In Russ.)]. doi: 10.14412/1995-4484- 2014-474-476

2. van der Linden SM, Valkenburg HA, de Jongh BM, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum. 1984;27(3):241-249. doi: 10.1002/art.1780270301-5

3. Khan MA, Ball EJ. Genetic aspects of ankylosing spondylitis. Best Pract Res Clin Rheumatol. 2002;16:675-690. doi: 10.1053/berh.2002.0243

4. Brown MA, Laval SH, Brophy S, Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2000;59:883-886. doi: 10.1136/ard.59.11.883

5. Australo-Anglo-American Spondyloarthritis Consortium (TASC), Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010;42(2):123-127. doi: 10.1038/ng.513

6. Lin Z, Bei JX, Shen M, Li Q, Liao Z, Zhang Y, et al. A genomewide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet. 2011;44(1):73-77. doi: 10.1038/ng.1005

7. Reveille JD. Biomarkers in axial spondyloarthritis and low back pain: A comprehensive review. Clin Rheumatol. 2022;41(3):617-634. doi: 10.1007/s10067-021-05968-1

8. Wullaert A, Bonnet MC, Pasparakis M. NF-kappaB in the regulation of epithelial homeostasis and inflammation. Cell Res. 2011;21:146-158. doi: 10.1038/cr.2010.175

9. Sun SC, Chang JH, Jin J. Regulation of nuclear factor-kappaB in autoimmunity. Trends Immunol. 2013;34:282-289. doi: 10.1016/j.it.2013.01.004

10. Liu X, Qin H, Wu J, Xu J. Association of TNFAIP3 and TNIP1 poly morphisms with systemic lupus erythematosus risk: A metaanalysis. Gene. 2018;668:155-165. doi: 10.1016/j.gene.2018.05.062

11. Allanore Y, Saad M, Dieudé P, Avouac J, Distler JH, Amouyel P, et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet. 2011;7(7): e1002091. doi: 10.1371/journal.pgen.1002091

12. Zhang L, Yuan X, Zhou Q, Shi J, Song Z, Quan R, et al. Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis risk: A meta-analysis. Arch Med Res. 2017;48(4):386-392. doi: 10.1016/j.arcmed.2017.08.003

13. Wang MJ, Yang HY, Zhang H, Zhou X, Liu RP, Mi YY. TNFAIP3 gene rs10499194, rs13207033 polymorphisms decrease the risk of rheumatoid arthritis. Oncotarget. 2016;7(50):82933-82942. doi: 10.18632/oncotarget.12638

14. Li XL, Yu H, Wu GS. Investigating the genetic association of HCP5, SPATA2, TNIP1, TNFAIP3 and COG6 with psoriasis in Chinese population. Int J Immunogenet. 2014;41:503-507. doi: 10.1111/iji.12150

15. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27:361-368. doi: 10.1002/art.1780270401

16. Guseva IA, Demidova NV, Soroka NE, Luchikhina EL, Novikov AA, Aleksandrova EN, et al. Investigation of candidate gene polymorphisms in an immune response as markers for the risk of developing rheumatoid arthritis and producing autoantibodies. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2016;54(1):21-30 (In Russ)]. doi: 10.14412/1995-4484-2016-21-30

17. Song RH, Yu ZY, Wang Q, Muhali FS, Jiang WJ, Xiao L, et al. Polymorphisms of the TNFAIP3 region and Graves’ disease. Autoimmunity. 2014;47(7):459-465. doi: 10.3109/08916934.2014.914504

18. Orozco G, Hinks A, Eyre S, Ke X, Gibbons LJ, Bowes J, et al. Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23. Hum Mol Genet. 2009;18(14): 2693-2699. doi: 10.1093/hmg/ddp193

19. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet. 2008;40(9): 1059-1061. doi: 10.1038/ng.200

20. Hoffjan S, Okur A, Epplen JT, Wieczorek S, Chan A, Akkad DA. Association of TNFAIP3 and TNFRSF1A variation with multiple sclerosis in a German case-control cohort. Int J Immunogenet. 2015;42(2):106-110. doi: 10.1111/iji.12183

21. Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J, et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet. 2007;39(12):1477-1482. doi: 10.1038/ng.2007.27

22. Prahalad S, Hansen S, Whiting A, Guthery SL, Clifford B, McNally B, et al. Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis. Arthritis Rheum. 2009;60(7):2124-2130. doi: 10.1002/art.24618

23. Yang J, Hu X, Wu M, Ma Y, Zhang X, Chen M, et al. TNFAIP3 genetic polymorphisms reduce ankylosing spondylitis risk in Eastern Chinese Han population. Sci Rep. 2019;9(1):10209. doi: 10.1038/s41598-019-46647-1

24. Zhang X, Li W, Zhang X, Zhao L, Zhang X, Jiang L, et al. Single nucleotide polymorphisms in TNFAIP3 were associated with the risks of rheumatoid arthritis in northern Chinese Han population. BMC Med Genet. 2014;15:56. doi: 10.1186/1471-2350-15-56

25. Gracey E, Yao Y, Green B, Qaiyum Z, Baglaenko Y, Lin A, et al. Sexual dimorphism in the Th17 signature of ankylosing spondylitis. Arthritis Rheumatol. 2016;68(3):679-689. doi: 10.1002/art.39464

26. Tsui HW, Inman RD, Reveille JD, Tsui FW. Association of a TNAP haplotype with ankylosing spondylitis. Arthritis Rheum. 2007;56(1): 234-243. doi: 10.1002/art.22307

27. Tsui HW, Inman RD, Paterson AD, Reveille JD, Tsui FW. ANKH variants associated with ankylosing spondylitis: Gender differences. Arthritis Res Ther. 2005;7(3):R513-R525. doi: 10.1186/ar1701

28. Zeboulon N, Dougados M, Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: A systematic literature review. Ann Rheum Dis. 2008;67(7):955-959. doi: 10.1136/ard.2007.075754

29. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: A systematic review and meta-analysis. Ann Rheum Dis. 2015;74(1):65-73. doi: 10.1136/annrheumdis2013-203582

30. de Carvalho HM, Bortoluzzo AB, Gonçalves CR, da Silva JA, Ximenes AC, Bértolo MB, et al.; Brazilian Registry on Spondyloarthritis. Gender characterization in a large series of Brazilian patients with spondyloarthritis. Clin Rheumatol. 2012;31(4):687-695. doi: 10.1007/s10067-011-1890-3