Association Study of CD226 and CD247 Genes Single Nucleotide Polymorphisms in Iranian Patients with Systemic Sclerosis
AbstractCD247 and CD226 play important roles in signaling of lymphocytes. Single nucleotide polymorphisms (SNPs) of genes encoding CD247 and CD226 have been associated with the risk of several autoimmune disorders. This study aimed to evaluate the possible association between CD226 and CD247 genes SNPs and risk of systemic sclerosis (SSc) in Iranian population. Study participants were 455 SSc patients and 455 age, sex and ethnic -matched healthy individuals. Genotyping of rs2056626 and rs763361 at CD247 and CD226 genes, respectively, was carried out using TaqMan MGB-based allelic discrimination real-time PCR. Neither alleles nor genotypes of both SNPs showed significant association with the risk of SSc. Furthermore, association analysis of the genotypes with clinical manifestations of the disease revealed that rs763361 variants were associated with the forced vital capacity (FVC) in SSc patients. Our results suggest that genetic variants of CD226 and CD247 genes may not be a contributing factor in pathogenesis of SSc in Iranian population.
1. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. The Journal of clinical investigation. 2007;117(3):557.2. Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis & Rheumatology. 2013;65(11):2737-47.3. Jafarinejad-Farsangi S, Farazmand A, Mahmoudi M, Gharibdoost F, Karimizadeh E, Noorbakhsh F, et al. MicroRNA-29a induces apoptosis via increasing the Bax: Bcl-2 ratio in dermal fibroblasts of patients with systemic sclerosis. Autoimmunity 2015; 48(6):369-78.4. Radstake TR, Gorlova O, Rueda B, Martin J-E, Alizadeh BZ, Palomino-Morales R, et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 2010; 42(5):426-9.5. Chairta P, Nicolaou P, Christodoulou K. Genomic and genetic studies of systemic sclerosis: A systematic review. Human Immunology 2017; 78(2):153-65.6. Aslani S, Mahmoudi M, Karami J, Jamshidi AR, Malekshahi Z, Nicknam MH. Epigenetic alterations underlying autoimmune diseases. Autoimmunity 2016; 49(2):69-83.7. Abtahi S, Farazmand A, Mahmoudi M, Ashraf‐Ganjouei A, Javinani A, Nazari B, et al. IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis. Int J Immunogenet 2015; 42(6):423-7.8. Vettori S, Cuomo G, Iudici M, D’Abrosca V, Giacco V, Barra G, et al. Early systemic sclerosis: serum profiling of factors involved in endothelial, T-cell, and fibroblast interplay is marked by elevated interleukin-33 levels. J Clin Immunol 2014; 34(6):663-8.9. Matucci‐Cerinic M, Kahaleh B, Wigley FM. Evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 2013; 65(8):1953-62.10. Jimenez SA, Piera-Velazquez S. Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of Systemic Sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality? Matrix Biol 2016; 51:26-36.11. Furue M, Mitoma C, Mitoma H, Tsuji G, Chiba T, Nakahara T, et al. Pathogenesis of systemic sclerosis current concept and emerging treatments. Immunol Res 2017; 65(4):1-8.12. O'reilly S. Role of interleukin‐13 in fibrosis, particularly systemic sclerosis. Biofactors 2013; 39(6):593-6.13. Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of disease: the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol 2006; 2(12):679-85.14. Irving BA, Chan AC, Weiss A. Functional characterization of a signal transducing motif present in the T cell antigen receptor zeta chain. J Exp Med 1993; 177(4):1093-103.15. Sussman JJ, Bonifacino JS, Lippincott-Schwartz J, Weissman AM, Saito T, Klausner RD, et al. Failure to synthesize the T cell CD3-ζ chain: structure and function of a partial T cell receptor complex. Cell 1988; 52(1):85-95.16. Rieux-Laucat F, Hivroz C, Lim A, Mateo V, Pellier I, Selz F, et al. Inherited and somatic CD3 ζ mutations in a patient with T-cell deficiency. N Engl J Med 2006; 354(18):1913-21.17. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39(7):857-64.18. Shibuya K, Shirakawa J, Kameyama T, Honda S-i, Tahara-Hanaoka S, Miyamoto A, et al. CD226 (DNAM-1) is involved in lymphocyte function–associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation. J Exp Med 2003; 198(12):1829-39.19. Maiti AK, Kim-Howard X, Viswanathan P, Guillén L, Qian X, Rojas-Villarraga A, et al. Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases. Rheumatology 2010; 49(7):1239-44.20. Löfgren SE, Delgado‐Vega AM, Gallant CJ, Sánchez E, Frostegård J, Truedsson L, et al. A 3′‐untranslated region variant is associated with impaired expression of CD226 in T and natural killer T cells and is associated with susceptibility to systemic lupus erythematosus. Arthritis Rheum 2010; 62(11):3404-14.21. Broen JC, Coenen MJ, Radstake TR. Genetics of systemic sclerosis: an update. Curr Rheumatol Rep 2012; 14(1):11-21.22. Jin J, Chou C, Lima M, Zhou D, Zhou X. Systemic sclerosis is a complex disease associated mainly with immune regulatory and inflammatory genes. Open Rheumatol J 2014; 8(1):29-42.23. Wells AU. Interstitial lung disease in systemic sclerosis. Presse Med 2014; 43(10):e329-e43.24. Luo Y, Wang Y, Wang Q, Xiao R, Lu Q. Systemic sclerosis: genetics and epigenetics. J Autoimmun 2013; 41:161-7.25. Balding DJ. A tutorial on statistical methods for population association studies. Nat Rev Genet 2006; 7(10):781.26. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning. A laboratory Manual. 2nd ed. New York: Cold Spring Harbor Laboratory Press; 1989.27. Diab S, Dostrovsky N, Hudson M, Tatibouet S, Fritzler MJ, Baron M, et al. Systemic sclerosis sine scleroderma: a multicenter study of 1417 subjects. J Rheumatol 2014; 41(11):2179-85.28. Distler O, Cozzio A. Systemic sclerosis and localized scleroderma--current concepts and novel targets for therapy. Semin Immunopathol 2016; 38(1):87-95.29. Jafarinejad‐Farsangi S, Farazmand A, Gharibdoost F, Karimizadeh E, Noorbakhsh F, Faridani H, et al. Inhibition of MicroRNA‐21 induces apoptosis in dermal fibroblasts of patients with systemic sclerosis. Int J Dermatol 2016; 55(11):1259-67.30. Karimizadeh E, Gharibdoost F, Motamed N, Jafarinejad-Farsangi S, Jamshidi A, Mahmoudi M. c-Abl silencing reduced the inhibitory effects of TGF-β1 on apoptosis in systemic sclerosis dermal fibroblasts. Mol Cell Biochem 2015; 405(1-2):169-76.31. Karimizadeh E, Motamed N, Mahmoudi M, Jafarinejad-Farsangi S, Jamshidi A, Faridani H, et al. Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts. Arch Dermatol Res 2015; 307(2):135-42.32. Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 2013; 65(8):1953-62.33. Fuschiotti P. Current perspectives on the immunopathogenesis of systemic sclerosis. I Immunotargets Ther 2016; 5:21-35.34. Mahmoudi M, Fallahian F, Sobhani S, Ghoroghi S, Jamshidi A, Poursani S, et al. Analysis of killer cell immunoglobulin-like receptors (KIRs) and their HLA ligand genes polymorphisms in Iranian patients with systemic sclerosis. Clin Rheumatol 2017; 36(4):853-62.35. Kalogerou A, Gelou E, Mountantonakis S, Settas L, Zafiriou E, Sakkas L. Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis 2005; 64(8):1233-5.36. Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi J-T, Pergamenschikov A, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A 2003; 100(21):12319-24.37. Sakkas LI, Platsoucas CD. Is systemic sclerosis an antigen‐driven T cell disease? Arthritis Rheum 2004; 50(6):1721-33.38. Mavalia C, Scaletti C, Romagnani P, Carossino AM, Pignone A, Emmi L, et al. Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol 1997; 151(6):1751.39. Sakkas LI, Tourtellotte C, Berney S, Myers AR, Platsoucas CD. Increased levels of alternatively spliced interleukin 4 (IL-4δ2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis. Clin Diagn Lab Immunol 1999; 6(5):660-4.40. Krishnan S, Kiang JG, Fisher CU, Nambiar MP, Nguyen HT, Kyttaris VC, et al. Increased caspase-3 expression and activity contribute to reduced CD3ζ expression in systemic lupus erythematosus T cells. J Immunol 2005; 175(5):3417-23.41. Krishnan S, Warke VG, Nambiar MP, Wong HK, Tsokos GC, Farber DL. Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression. Blood 2001; 97(12):3851-9.42. Krishnan S, Warke VG, Nambiar MP, Tsokos GC, Farber DL. The FcRγ subunit and Syk kinase replace the CD3ζ-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells. J Immunol 2003; 170(8):4189-95.43. Gorman CL, Russell AI, Zhang Z, Graham DC, Cope AP, Vyse TJ. Polymorphisms in the CD3Z gene influence TCRζ expression in systemic lupus erythematosus patients and healthy controls. J Immunol 2008; 180(2):1060-70.44. Warchoł T, Piotrowski P, Lianeri M, Cieślak D, Wudarski M, Hrycaj P, et al. The CD3Z 844 T> A polymorphism within the 3′‐UTR of CD3Z confers increased risk of incidence of systemic lupus erythematosus. Tissue Antigens 2009; 74(1):68-72.45. Dieudé P, Boileau C, Guedj M, Avouac J, Ruiz B, Hachulla E, et al. Independent replication establishes the CD247 gene as a genetic systemic sclerosis susceptibility factor. Ann Rheum Dis 2011; 70(9):1695-6.46. Wang J, Yi L, Guo X, He D, Li H, Guo G, et al. Lack of association of the CD247 SNP rs2056626 with systemic sclerosis in Han Chinese. Open Rheumatol J 2014; 8(1):43-5.47. Lundholm M, Mayans S, Motta V, Lofgren-Burstrom A, Danska J, Holmberg D. Variation in the Cd3 zeta (Cd247) gene correlates with altered T cell activation and is associated with autoimmune diabetes. J Immunol 2010; 184(10):5537-44.48. Dieude P, Guedj M, Truchetet M-E, Wipff J, Revillod L, Riemekasten G, et al. Association of the CD226 Ser307 variant with systemic sclerosis: Evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis. Arthritis Rheum 2011; 63(4):1097-105.49. Bossini-Castillo L, Simeon CP, Beretta L, Broen JC, Vonk MC, Ríos-Fernández R, et al. A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis. Arthritis Res Ther 2012; 14(2):85.50. Liu R, Xu N, Wang X, Shen L, Zhao G, Zhang H, et al. Influence of MIF, CD40, and CD226 polymorphisms on risk of rheumatoid arthritis. Mol Biol Rep 2012; 39(6):6915-22.51. Du Y, Shen LX, Yu LK, Song Y, Zhu JF, Du R. The CD226 gene in susceptibility of rheumatoid arthritis in the Chinese Han population. Rheumatol Int 2012; 32(5):1299-304.52. Du Y, Tian L, Shen L, Wang F, Yu L, Song Y, et al. Association of the CD226 single nucleotide polymorphism with systemic lupus erythematosus in the Chinese Han population. Tissue antigens 2011; 77(1):65-7.53. Song G, Bae S, Choi S, Ji J, Lee Y. Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune diseases: a meta-analysis. Lupus 2012; 21(14):1522-30.54. Michelfelder M, Becker M, Riedlinger A, Siegert E, Dromann D, Yu X, et al. Interstitial lung disease increases mortality in systemic sclerosis patients with pulmonary arterial hypertension without affecting hemodynamics and exercise capacity. Clin Rheumatol 2016; 36(2):381-90.55. Man A, Davidyock T, Ferguson LT, Ieong M, Zhang Y, Simms RW. Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling. Rheumatology (Oxford) 2015; 54(8):1464-71.