Bo XU, Xiao-Qing SHİ, Run-lin XING, Yan-Cheng XİAO, Peng WU, Pei-Min WANG

Meta-analysis of the association of IL1-RN variable number of tandem repeats polymorphism with osteoarthritis risk

Objective: The aim of this meta-analysis was to clarify the role of Interleukin-1 receptor antagonist gene (IL1-RN) Variable Number of Tandem Repeats (VNTR) polymorphism on the risk of OA by means of metaanalysis. Methods: Eligible articles were retrieved from PubMed, Web of science and Google scholar with a total of 1187 OA cases and 2659 controls. The strength of the association between the IL1-RN VNTR polymorphism and the risk of OA was assessed by odds ratios (ORs) with the corresponding 95% confidence interval (CI) for each study. Results: The meta-analysis of seven published studies retrieved from the literature search showed a significantly increased OA risk in the recessive model analysis (22 vs 2L þ LL: Pb ¼ 0.18, I2 ¼ 32.8, OR(95% CI) ¼ 1.50(1.12, 2.02), P ¼ 0.007), the additive model analysis (22 vs LL: Pb ¼ 0.08, I2 ¼ 46.8, OR(95% CI) ¼ 1.56(1.15, 2.12), P ¼ 0.004) and in the allele contrast model (2 vs L: Pb ¼ 0.02, I2 ¼ 58.8, OR(95% CI) ¼ 1.20(1.05, 1.36), P ¼ 0.007). By subgroup analysis, the IL1-RN VNTR polymorphism was found to be significantly associated with OA susceptibility in Caucasian and Hospital based case-control study (HCC) groups. Conclusion: This meta-analysis showed that IL1-RN VNTR polymorphism may increase the susceptibility to OA. More studies with detailed information are needed to validate our conclusion.

___

1. Higgs R. Osteoarthritis: concentrated efforts to detect early OA. Nat Rev Rheumatol. 2010;6(11):616.

2. Loeser RF, Goldring SR, Scanzello CR, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697e1707.

3. Nakamura H, Yoshino S, Kato T, et al. T-cell mediated inflammatory pathway in osteoarthritis. Osteoarthritis Cartilage. 1999;7(4):401e402.

4. Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology. 2002;39(1e2):237e246.

5. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010;10(2):89e102.

6. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018;281(1):8e27.

7. Cai L, Zhang JW, Xue XX, et al. Meta-analysis of associations of IL1 receptor antagonist and estrogen receptor gene polymorphisms with systemic lupus erythematosus susceptibility. PLoS One. 2014;9(10):1e10.

8. Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol. 1998;47(3):195e198.

9. Sezgin M, Erdal ME, Altintas ZM, et al. Lack of association polymorphisms of the IL1RN, IL1A, and IL1B genes with knee osteoarthritis in Turkish patients. Clin Invest Med. 2007;30(2):E86eE92.

10. Jotanovic Z, Etokebe GE, Mihelic R, et al. IL1B -511(G>A) and IL1RN (VNTR) allelic polymorphisms and susceptibility to knee osteoarthritis in Croatian population. Rheumatol Int. 2012;32(7):2135e2141.

11. Jotanovic Z, Etokebe GE, Mihelic R, et al. Hip osteoarthritis susceptibility is associated with IL1B -511(G>A) and IL1 RN (VNTR) genotypic polymorphisms in Croatian Caucasian population. J Orthop Res. 2011;29(8):1137e1144.

12. Ni H, Shi D, Dai J, et al. Genetic polymorphisms of interleukin-1beta (-511C/T) and interleukin-1 receptor antagonist (86-bpVNTR) in susceptibility to knee osteoarthritis in a Chinese Han population. Rheumatol Int. 2009;29(11):1301e1305.

13. Meulenbelt I, Seymour AB, Nieuwland M, et al. Association of the interleukin-1 gene cluster with radiographic signs of osteoarthritis of the hip. Arthritis Rheum. 2004;50(4):1179e1186.

14. Stern AG, de Carvalho MR, Buck GA, et al. Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta. Osteoarthritis Cartilage. 2003;11(6):394e402.

15. Moos V, Rudwaleit M, Herzog V, et al. Association of genotypes affecting the expression of interleukin-1beta or interleukin-1 receptor antagonist with osteoarthritis. Arthritis Rheum. 2000;43(11):2417e2422.

16. Peach CA, Carr AJ, Loughlin J. Recent advances in the genetic investigation of osteoarthritis. Trends Mol Med. 2005;11(4):186e191.

17. Sharma L. Local factors in osteoarthritis. Curr Opin Rheumatol. 2001;13(5): 441e446.

18. Sowers M. Epidemiology of risk factors for osteoarthritis: systemic factors. Curr Opin Rheumatol. 2001;13(5):447e451.

19. Berenbaum F, Eymard F, Houard X. Osteoarthritis, inflammation and obesity. Curr Opin Rheumatol. 2013;25(1):114e118.

20. Eisenberg SP, Evans RJ, Arend WP, et al. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990;343(6256):341e346.

21. Sims JE, Dower SK. Interleukin-1 receptors. Eur Cytokine Netw. 1994;5(6): 539e546.

22. Taylor SL, Renshaw BR, Garka KE, et al. Genomic organization of the interleukin-1 locus. Genomics. 2002;79(5):726e733.

23. Garat C, Arend WP. Intracellular IL-1Ra type 1 inhibits IL-1-induced IL-6 and IL8 production in Caco-2 intestinal epithelial cells through inhibition of p38 mitogen-activated protein kinase and NF-kappaB pathways. Cytokine. 2003;23(1e2):31e40.

24. Vamvakopoulos J, Green C, Metcalfe S. Genetic control of IL-1beta bioactivity through differential regulation of the IL-1 receptor antagonist. Eur J Immunol. 2002;32(10):2988e2996.

25. Lim WY, Chen Y, Ali SM, et al. Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers. Carcinogenesis. 2011;32(4):522e529.

26. Korthagen NM, van Moorsel CH, Kazemier KM, et al. IL1RN genetic variations and risk of IPF: a meta-analysis and mRNA expression study. Immunogenetics. 2012;64(5):371e377.