Abstract
Regulatory T cells (Tregs) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important Treg marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (PFDR=2.07 × 10−4, odds ratio=1.30 (1.14–1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.
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References
Malek TR . The biology of interleukin-2. Annu Rev Immunol 2008; 26: 453–479.
Burchill MA, Yang J, Vang KB, Farrar MA . Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. Immunol Lett 2007; 114: 1–8.
Buckner JH . Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol 2010; 10: 849–859.
Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 2007; 39: 1074–1082.
Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 2010; 42: 508–514.
Carr EJ, Clatworthy MR, Lowe CE, Todd JA, Wong A, Vyse TJ et al. Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis. BMC Med Genet 2009; 10: 22.
Wang J, Wicker LS, Santamaria P . IL-2 and its high-affinity receptor: genetic control of immunoregulation and autoimmunity. Semin Immunol 2009; 21: 363–371.
Zhernakova A, van Diemen CC, Wijmenga C . Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 2009; 10: 43–55.
Assassi S, Mayes MD, Arnett FC, Gourh P, Agarwal SK, McNearney TA et al. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum 2010; 62: 589–598.
Martin J, Fonseca C . The genetics of scleroderma. Curr Rheumatol Rep 2011; 13: 13–20.
Katsumoto TR, Whitfield ML, Connolly MK . The pathogenesis of systemic sclerosis. Annu Rev Pathol 2011; 6: 509–537.
LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger Jr TA et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988; 15: 202–205.
Ihn H, Sato S, Fujimoto M, Kikuchi K, Takehara K . Clinical significance of serum levels of soluble interleukin-2 receptor in patients with localized scleroderma. Br J Dermatol 1996; 134: 843–847.
Steen VD, Engel EE, Charley MR, Medsger Jr∣ TA . Soluble serum interleukin 2 receptors in patients with systemic sclerosis. J Rheumatol 1996; 23: 646–649.
Maier LM, Lowe CE, Cooper J, Downes K, Anderson DE, Severson C et al. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production. PLoS Genet 2009; 5: e1000322.
Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.
Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 2008; 359: 2767–2777.
Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW . Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995; 3: 521–530.
Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 1995; 268: 1472–1476.
Radstake TR, van Bon L, Broen J, Wenink M, Santegoets K, Deng Y et al. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGF beta expression. PLoS One 2009; 4: e5981.
Klein S, Kretz CC, Ruland V, Stumpf C, Haust M, Hartschuh W et al. Reduction of regulatory T cells in skin lesions but not in peripheral blood of patients with systemic scleroderma. Ann Rheum Dis 2011; 70: 1475–1481.
Dendrou CA, Plagnol V, Fung E, Yang JH, Downes K, Cooper JD et al. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat Genet 2009; 41: 1011–1015.
Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980; 23: 581–590.
LeRoy EC, Medsger Jr TA . Criteria for the classification of early systemic sclerosis. J Rheumatol 2001; 28: 1573–1576.
Bossini-Castillo L, Broen JC, Simeon CP, Beretta L, Vonk MC, Ortego-Centeno N et al. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort. Ann Rheum Dis 2011; 70: 638–641.
Skol AD, Scott LJ, Abecasis GR, Boehnke M . Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 2006; 38: 209–213.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 1995; 57: 289–300.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Acknowledgements
We thank Sofía Vargas, Sonia García and Gema Robledo for their excellent technical assistance, and all the patients and healthy controls for kindly accepting their essential collaboration. Banco Nacional de ADN (University of Salamanca, Spain) and The Norwegian Bone Marrow Donor Registry are thanked for supplying part of the control material. We are also thankful to EUSTAR and the German Network of Systemic Sclerosis for the facilitation of this project. This work was supported by the following grants: JM was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 and CTS-180 from Junta de Andalucía, and in part by RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain. FDC was supported by Consejo Superior de Investigaciones Científicas (CSIC) through the program JAE-DOC. TRDJR was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). CF is supported by ‘The Raynaud's and Scleroderma Association’ and ‘The Scleroderma Society’. JM and TRDJR were sponsored by the Orphan Disease Program grant from EULAR. TW was granted by DFG WI 1031/6.1.
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Martin, JE., Carmona, F., Broen, J. et al. The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis. Genes Immun 13, 191–196 (2012). https://doi.org/10.1038/gene.2011.72
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DOI: https://doi.org/10.1038/gene.2011.72
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