Iranian Journal of Allergy, Asthma and Immunology 2017. 16(6):471-479.

Association Study of CD226 and CD247 Genes Single Nucleotide Polymorphisms in Iranian Patients with Systemic Sclerosis
Fatemeh Abbasi, Reza Mansouri, Farhad Gharibdoost, Saeed Aslani, Shayan Mostafaei, Hoda Kavosi, Shiva Poursani, Soheila Sobhani, Mahdi Mahmoudi


CD247 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.


CD226; CD247; Single nucleotide polymorphism; Systemic sclerosis

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1.         SSc DC. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. The Journal of rheumatology. 1988;15:23.

2.         Masi AT. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis & Rheumatism. 1980;23(5):581-90.

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. Nature genetics. 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.         Irving BA, Chan AC, Weiss A. Functional characterization of a signal transducing motif present in the T cell antigen receptor zeta chain. Journal of Experimental Medicine. 1993;177(4):1093-103.

7.         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.

8.         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. New England Journal of Medicine. 2006;354(18):1913-21.

9.         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. Nature genetics. 2007;39(7):857-64.

10.       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. Journal of experimental medicine. 2003;198(12):1829-39.

11.       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.

12.       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 & Rheumatism. 2010;62(11):3404-14.

13.       Broen JC, Coenen MJ, Radstake TR. Genetics of systemic sclerosis: an update. Current rheumatology reports. 2012;14(1):11-21.

14.       Jin J, Chou C, Lima M, Zhou D, Zhou X. Systemic sclerosis is a complex disease associated mainly with immune regulatory and inflammatory genes. The open rheumatology journal. 2014;8(1).

15.       Wells AU. Interstitial lung disease in systemic sclerosis. La Presse Médicale. 2014;43(10):e329-e43.

16.       Luo Y, Wang Y, Wang Q, Xiao R, Lu Q. Systemic sclerosis: genetics and epigenetics. Journal of autoimmunity. 2013;41:161-7.

17.       Glover DM, Hames BD. DNA cloning 3: a practical approach: IRL Press Ltd; 1995.

18.       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.

19.       Distler O, Cozzio A. Systemic sclerosis and localized scleroderma--current concepts and novel targets for therapy. Seminars in immunopathology. 2016;38(1):87-95.

20.       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. International Journal of Dermatology. 2016;55(11):1259-67.

21.       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. Molecular and cellular biochemistry. 2015;405(1-2):169-76.

22.       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. Archives of dermatological research. 2015;307(2):135-42.

23.       Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis and rheumatism. 2013;65(8):1953-62.

24.       Fuschiotti P. Current perspectives on the immunopathogenesis of systemic sclerosis. ImmunoTargets and therapy. 2016;5:21-35.

25.       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. Clinical rheumatology. 2017;36(4):853-62.

26.       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 & Rheumatism. 2011;63(4):1097-105.

27.       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 research & therapy. 2012;14(2):1.

28.       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. Molecular biology reports. 2012;39(6):6915-22.

29.       Du Y, Shen L-X, Yu L-K, Song Y, Zhu J-F, Du R. The CD226 gene in susceptibility of rheumatoid arthritis in the Chinese Han population. Rheumatology international. 2012;32(5):1299-304.

30.       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.

31.       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.

32.       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. Annals of the rheumatic diseases. 2011;70(9):1695-6.

33.       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. The open rheumatology journal. 2014;8(1).

34.       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. Journal of immunology (Baltimore, Md : 1950). 2010;184(10):5537-44.

35.       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. Clinical rheumatology. 2016.

36.       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, England). 2015;54(8):1464-71.


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