OBJECTIVE: Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. METHODS: Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA. CONCLUSION: We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.
OBJECTIVE: Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. METHODS: Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA. CONCLUSION: We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.
Authors: Hironori Ueda; Joanna M M Howson; Laura Esposito; Joanne Heward; Hywel Snook; Giselle Chamberlain; Daniel B Rainbow; Kara M D Hunter; Annabel N Smith; Gianfranco Di Genova; Mathias H Herr; Ingrid Dahlman; Felicity Payne; Deborah Smyth; Christopher Lowe; Rebecca C J Twells; Sarah Howlett; Barry Healy; Sarah Nutland; Helen E Rance; Vin Everett; Luc J Smink; Alex C Lam; Heather J Cordell; Neil M Walker; Cristina Bordin; John Hulme; Costantino Motzo; Francesco Cucca; J Fred Hess; Michael L Metzker; Jane Rogers; Simon Gregory; Amit Allahabadia; Ratnasingam Nithiyananthan; Eva Tuomilehto-Wolf; Jaakko Tuomilehto; Polly Bingley; Kathleen M Gillespie; Dag E Undlien; Kjersti S Rønningen; Cristian Guja; Constantin Ionescu-Tîrgovişte; David A Savage; A Peter Maxwell; Dennis J Carson; Chris C Patterson; Jayne A Franklyn; David G Clayton; Laurence B Peterson; Linda S Wicker; John A Todd; Stephen C L Gough Journal: Nature Date: 2003-04-30 Impact factor: 49.962
Authors: Robert M Plenge; Chris Cotsapas; Leela Davies; Alkes L Price; Paul I W de Bakker; Julian Maller; Itsik Pe'er; Noel P Burtt; Brendan Blumenstiel; Matt DeFelice; Melissa Parkin; Rachel Barry; Wendy Winslow; Claire Healy; Robert R Graham; Benjamin M Neale; Elena Izmailova; Ronenn Roubenoff; Alexander N Parker; Roberta Glass; Elizabeth W Karlson; Nancy Maher; David A Hafler; David M Lee; Michael F Seldin; Elaine F Remmers; Annette T Lee; Leonid Padyukov; Lars Alfredsson; Jonathan Coblyn; Michael E Weinblatt; Stacey B Gabriel; Shaun Purcell; Lars Klareskog; Peter K Gregersen; Nancy A Shadick; Mark J Daly; David Altshuler Journal: Nat Genet Date: 2007-11-04 Impact factor: 38.330
Authors: Lindsey A Criswell; Kirsten A Pfeiffer; Raymond F Lum; Bonnie Gonzales; Jill Novitzke; Marlena Kern; Kathy L Moser; Ann B Begovich; Victoria E H Carlton; Wentian Li; Annette T Lee; Ward Ortmann; Timothy W Behrens; Peter K Gregersen Journal: Am J Hum Genet Date: 2005-02-17 Impact factor: 11.025
Authors: Ingrid E Wertz; Karen M O'Rourke; Honglin Zhou; Michael Eby; L Aravind; Somasekar Seshagiri; Ping Wu; Christian Wiesmann; Rohan Baker; David L Boone; Averil Ma; Eugene V Koonin; Vishva M Dixit Journal: Nature Date: 2004-07-18 Impact factor: 49.962
Authors: H M Albers; F A S Kurreeman; J J Houwing-Duistermaat; D M C Brinkman; S S M Kamphuis; H J Girschick; C Wouters; M A J Van Rossum; W Verduijn; R E M Toes; T W J Huizinga; M W Schilham; R ten Cate Journal: Ann Rheum Dis Date: 2008-07-01 Impact factor: 19.103
Authors: Kimberly E Taylor; Elaine F Remmers; Annette T Lee; Ward A Ortmann; Robert M Plenge; Chao Tian; Sharon A Chung; Joanne Nititham; Geoffrey Hom; Amy H Kao; F Yesim Demirci; M Ilyas Kamboh; Michelle Petri; Susan Manzi; Daniel L Kastner; Michael F Seldin; Peter K Gregersen; Timothy W Behrens; Lindsey A Criswell Journal: PLoS Genet Date: 2008-05-30 Impact factor: 5.917
Authors: Anne Barton; Wendy Thomson; Xiayi Ke; Steve Eyre; Anne Hinks; John Bowes; Laura Gibbons; Darren Plant; Anthony G Wilson; Ioanna Marinou; Ann Morgan; Paul Emery; Sophia Steer; Lynne Hocking; David M Reid; Paul Wordsworth; Pille Harrison; Jane Worthington Journal: Hum Mol Genet Date: 2008-04-22 Impact factor: 6.150
Authors: Susan D Thompson; Marc Sudman; Paula S Ramos; Miranda C Marion; Mary Ryan; Monica Tsoras; Tracey Weiler; Michael Wagner; Mehdi Keddache; J Peter Haas; Cornelia Mueller; Sampath Prahalad; John Bohnsack; Carol A Wise; Marilynn Punaro; Dongping Zhang; Carlos D Rosé; Mary E Comeau; Jasmin Divers; David N Glass; Carl D Langefeld Journal: Arthritis Rheum Date: 2010-11
Authors: Sampath Prahalad; Karen N Conneely; Yunxuan Jiang; Marc Sudman; Carol A Wallace; Milton R Brown; Lori A Ponder; Mina Rohani-Pichavant; Michael E Zwick; David J Cutler; Sheila T Angeles-Han; Larry B Vogler; Christine Kennedy; Kelly Rouster-Stevens; Carol A Wise; Marilynn Punaro; Ann M Reed; Elizabeth D Mellins; John F Bohnsack; David N Glass; Susan D Thompson Journal: Arthritis Rheum Date: 2013-06