Abstract
Juvenile idiopathic arthritis (JIA), the most common cause of chronic arthritis in children, is believed to be influenced by genetic factors. Recent studies on the genetics of JIA have not only validated proposed genetic associations but have also led to the recognition of novel genetic associations. Studies of specific genes have been modeled on the premise of shared autoimmunity, wherein genetic variants that predispose to other autoimmune phenotypes may also confer susceptibility to JIA. The advent of genome-wide association studies has accelerated the detection of non-HLA susceptibility loci in other autoimmune phenotypes and is likely to uncover novel JIA-associated variants as well. This review highlights recent genetic investigations of JIA.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Ravelli A, Martini A: Juvenile idiopathic arthritis. Lancet 2007, 369:767–778.
Petty RE, Southwood TR, Manners P, et al.: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004, 31:390–392.
Clemens LE, Albert E, Ansell BM: Sibling pairs affected by chronic arthritis of childhood: evidence for a genetic predisposition. J Rheumatol 1985, 12:108–113.
Moroldo MB, Tague BL, Shear ES, et al.: Juvenile rheumatoid arthritis in affected sibpairs. Arthritis Rheum 1997, 40:1962–1966.
Prahalad S: Genetic analysis of juvenile rheumatoid arthritis: approaches to complex traits. Curr Probl Pediatr Adolesc Health Care 2006, 36:83–90.
Glass DN, Giannini EH: Juvenile rheumatoid arthritis as a complex genetic trait. Arthritis Rheum 1999, 42:2261–2268.
• Prahalad S, Glass DN: A comprehensive review of the genetics of juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2008, 6:11. This is a comprehensive systematic review of more than 100 non-HLA genetic associations in JIA.
• Plenge RM: Rheumatoid arthritis genetics: 2009 update. Curr Rheumatol Rep 2009, 11:351–356. This review article describes updates on RA genetics.
Prahalad S, Ryan MH, Shear ES, et al.: Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs. Arthritis Rheum 2000, 43:2335–2338.
Prahalad S: Genetics of juvenile idiopathic arthritis: an update. Curr Opin Rheumatol 2004, 16:588–594.
Phelan JD, Thompson SD, Glass DN: Susceptibility to JRA/JIA: complementing general autoimmune and arthritis traits. Genes Immun 2006, 7:1–10.
• Macaubas C, Nguyen K, Milojevic D, et al.: Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat Rev Rheumatol 2009, 5:616–626. This review describes the epidemiology, genetics, and pathogenesis of JIA.
Watford WT, Hissong BD, Bream JH, et al.: Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 2004, 202:139–156.
Remmers EF, Plenge RM, Lee AT, et al.: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007, 357:977–986.
Barton A, Thomson W, Ke X, et al.: Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008, 17:2274–2279.
Martinez A, Varade J, Marquez A, et al.: Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 2008, 58:2598–2602.
Taylor KE, Remmers EF, Lee AT, et al.: Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 2008, 4:e1000084.
• Fung EY, Smyth DJ, Howson JM, et al.: Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 2009, 10:188–191. This was a case-control study of several autoimmune variants in a large T1D cohort.
•• Prahalad S, Hansen S, Whiting A, et al.: Variants in TNFAIP3, STAT4, and c12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis. Arthritis Rheum 2009, 60:2124–2130. This recent study describes various non-HLA associations with JIA.
•• Hinks A, Eyre S, Ke X, et al.: Overlap of disease susceptibility loci for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Ann Rheum Dis 2009 Aug 11 (Epub ahead of print). This was a second study that investigated nine candidate loci for association with JIA using a large JIA cohort.
Plenge RM, Cotsapas C, Davies L, et al.: Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007, 39:1477–1482.
Plenge RM, Seielstad M, Padyukov L, et al.: TRAF1-c5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med 2007, 357:1199–1209.
Kurreeman FA, Padyukov L, Marques RB, et al.: A candidate gene approach identifies the TRAF1/c5 region as a risk factor for rheumatoid arthritis. PLoS Med 2007, 4:e278. (Published erratum appears in PLoS Med 2007, 4:e358.)
Albers HM, Kurreeman FA, Houwing-Duistermaat JJ, et al. The TRAF1/c5 region is a risk factor for polyarthritis in juvenile idiopathic arthritis. Ann Rheum Dis 2008, 67:1578–1580.
Behrens EM, Finkel TH, Bradfield JP, et al.: Association of the TRAF1-c5 locus on chromosome 9 with juvenile idiopathic arthritis. Arthritis Rheum 2008, 58:2206–2207.
Sakaguchi S, Sakaguchi N, Asano M, et al.: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995, 155:1151–1164.
•• Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447:661–678. This was a large GWAS in which 17,000 individuals with seven phenotypes and also controls were typed for more than 500,000 SNPs.
Hafler DA, Compston A, Sawcer S, et al.: Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007, 357:851–862.
• Hinks A, Ke X, Barton A, et al.: Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis. Arthritis Rheum 2009, 60:251–257. This association study of IL2RA included a replication cohort from North America.
Barton A, Eyre S, Ke X, et al.: Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum Mol Genet 2009, 18:2518–2522.
Coenen MJ, Gregersen PK: Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun 2009, 10:101–111.
Plenge RM, Padyukov L, Remmers EF, et al.: Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: Association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 2005, 77:1044–1060.
Martinez A, Perdigones N, Cenit MC, et al.: Chromosomal region 16p13: further evidence of increased predisposition to immune diseases. Ann Rheum Dis 2010, 69:309–311.
McGreal EP, Martinez-Pomares L, Gordon S: Divergent roles for c-type lectins expressed by cells of the innate immune system. Mol Immunol 2004, 41:1109–1121.
• Skinningsrud B, Lie BA, Husebye ES, et al.: A CLEC16A variant confers risk for juvenile idiopathic arthritis and anti-CCP negative rheumatoid arthritis. Ann Rheum Dis 2009 Sep 3 (Epub ahead of print). This was an association study of a CLEC16A variant with RA, JIA, T1D, and Addison’s disease.
Plenge RM: Recent progress in rheumatoid arthritis genetics: one step towards improved patient care. Curr Opin Rheumatol 2009, 21:262–271.
Irigoyen P, Lee AT, Wener MH, et al.: Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum 2005, 52:3813–3818.
Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, et al.: Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum 2005, 52:3058–3062.
Sigurdsson S, Padyukov L, Kurreeman FA, et al.: Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum 2007, 56:2202–2210.
Albers HM, Kurreeman FA, Stoeken-Rijsbergen G, et al.: Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis. Arthritis Rheum 2009, 60:901–904.
Day TG, Ramanan AV, Hinks A, et al.: Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritis. Arthritis Rheum 2008, 58:2142–2146.
Gergely P Jr, Pazar B, Nagy ZB, et al.: Structural polymorphisms in the mannose-binding lectin gene are associated with juvenile idiopathic arthritis. J Rheumatol 2009, 36:843–847.
Yao TC, Tsai YC, Huang JL: Association of RANTES promoter polymorphism with juvenile rheumatoid arthritis. Arthritis Rheum 2009, 60:1173–1178.
Luster AD: Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 1998, 338:436–445.
Zeng HS, Chen XY, Luo XP: The association with the -159c/t polymorphism in the promoter region of the CD14 gene and juvenile idiopathic arthritis in a Chinese Han population. J Rheumatol 2009, 36:2025–2028.
Pugin J, Heumann ID, Tomasz A, et al.: CD14 is a pattern recognition receptor. Immunity 1994, 1:509–516.
Jimenez-Morales S, Velazquez-Cruz R, Ramirez-Bello J, et al.: Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population. Hum Immunol 2009, 70:251–256.
Altshuler D, Daly MJ, Lander ES: Genetic mapping in human disease. Science 2008, 322:881–888.
•• Hinks A, Barton A, Shephard N, et al.: Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis. Arthritis Rheum 2009, 60:258–263. This was the first GWAS in JIA.
Pont-Kingdon G, Bohnsack J, Sumner K, et al.: Lack of association between beta 2-adrenergic receptor polymorphisms and juvenile idiopathic arthritis. Scand J Rheumatol 2009, 38:91–95.
Acknowledgment
This work is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23-AR50177), the Arthritis Foundation, and the Rooms To Go foundation, Atlanta, GA.
Disclosure
No potential conflicts of interest relevant to this article were reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Angeles-Han, S., Prahalad, S. The Genetics of Juvenile Idiopathic Arthritis: What Is New in 2010?. Curr Rheumatol Rep 12, 87–93 (2010). https://doi.org/10.1007/s11926-010-0087-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11926-010-0087-0