Anti-IL21 Monoclonal antibody, clone 4B4-O3 [PE]

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 x 10(-12)], rs2476601 [OR 1.64, P = 1.90 x 10(-13)], and rs2488457 [OR 1.32, P = 6.74 x 10(-8)]), PTPN2 (rs1893217 [OR = 1.33, P = 1.60 x 10(-9)] and rs7234029 [OR 1.35, P = 1.86 x 10(-10)]), ADAD1-IL2-IL21 (rs17388568 [OR 1.24, P = 1.13 x 10(-6)] and rs13143866 [OR 0.83, P = 1.95 x 10(-4)]), STAT4 (rs3821236 [OR = 1.27, P = 2.36 x 10(-6)] and rs7574865 [OR = 1.31, P = 2.21 x 10(-6)]), C12orf30 (rs17696736 [OR = 1.19, P = 2.59 x 10(-5)]), COG6 (rs7993214 [OR = 0.76, P = 1.10 x 10(-5)]), and ANGPT1 (rs1010824 [OR = 0.79, P = 2.91 x 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 auto-immunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms.

Several confirmed genetic susceptibility loci involved in the interferon signaling and Th17/B cell response for SLE in Chinese Han populations have been described. Available data also indicate that sex-specific genetic differences contribute to SLE susceptibility. The aim of this study was to test for gene-gene/gene-sex epistasis (interactions) in these known lupus susceptibility loci. Six single-nucleotide polymorphisms (SNPs) in MiR146a, IRF5, IKZF1, ETS1 and IL21 were genotyped by Sequenom MassArray system. A total of 1,825 subjects (858 SLE patients and 967 controls) were included in the final analysis. Epistasis was tested by additive model, multiplicative model and multifactor dimensionality reduction (MDR) method. Additive interaction analysis revealed interactions between IRF5 and IKZF1 (OR 2.26, 95% CI 1.48-3.44 [P = 1.21x10(4)]). A similar tendency was also observed between IL21 and ETS1 by parametric methods. In addition, multiple high dimensional gene-gene or gene-sex interactions (three-and four-way) were identified by MDR analysis. Our study identified novel gene-gene/gene-sex interactions in lupus. Furthermore, these findings highlight sex, interferon pathway, and Th17/B cells as important contributors to the pathogenesis of SLE.