The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1

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. GlassCarl D. Langefeld

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Abstract

Objective To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA). Methods Published autoimmune disease genome-wide association studies were reviewed, and 519 single-nucleotide polymorphisms (SNPs) were selected for association testing. The initial cohort included 809 JIA cases and 3,535 controls of non-Hispanic, European ancestry. Of the SNPs, 257 were successfully genotyped, while 168 were imputed with quality. Based on findings in the initial cohort, replication was sought for 21 SNPs in a second cohort of 1,015 JIA cases and 1,569 controls collected in the US and Germany. For the initial cohort, tests for association were adjusted for potential confounding effects of population structure by including principal components derived from a genome-wide association study as covariates in logistic regression models. Odds ratios (ORs) and 95% confidence intervals were calculated. Results Testing for association of previously reported autoimmune disease genetic associations in the initial cohort suggested associations with JIA in 13 distinct loci. Of these, 7 were validated in the replication cohort. Meta-analysis results for the replicating loci included PTPN22 (rs6679677 [OR 1.58, P = 1.98 - 10-12], rs2476601 [OR 1.64, P = 1.90 - 10 -13], and rs2488457 [OR 1.32, P = 6.74 - 10-8]), PTPN2 (rs1893217 [OR = 1.33, P = 1.60 - 10-9] and rs7234029 [OR 1.35, P = 1.86 - 10-10]), ADAD1-IL2-IL21 (rs17388568 [OR 1.24, P = 1.13 - 10-6] and rs13143866 [OR 0.83, P = 1.95 - 10-4]), STAT4 (rs3821236 [OR = 1.27, P = 2.36 - 10-6] and rs7574865 [OR = 1.31, P = 2.21 - 10-6]), C12orf30 (rs17696736 [OR = 1.19, P = 2.59 - 10 -5]), COG6 (rs7993214 [OR = 0.76, P = 1.10 - 10-5]), and ANGPT1 (rs1010824 [OR = 0.79, P = 2.91 - 10-4]). These polymorphisms have been reported in diseases such as rheumatoid arthritis, type 1 diabetes mellitus, Crohn's disease, and multiple sclerosis. Conclusion General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms.

Original languageEnglish (US)
Pages (from-to)3265-3276
Number of pages12
JournalArthritis and rheumatism
Volume62
Issue number11
DOIs
StatePublished - Nov 1 2010

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Thompson, S. D., Sudman, M., Ramos, P. S., Marion, M. C., Ryan, M., Tsoras, M., Weiler, T., Wagner, M., Keddache, M., Haas, J. P., Mueller, C., Prahalad, S., Bohnsack, J., Wise, C. A., Punaro, M., Zhang, D., Rosé, C. D., Comeau, M. E., Divers, J., ... Langefeld, C. D. (2010). The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1. Arthritis and rheumatism, 62(11), 3265-3276. https://doi.org/10.1002/art.27688