Dataset Information

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

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.

SUBMITTER: Thompson SD

PROVIDER: S-EPMC2970764 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Thompson Susan D SD Sudman Marc M Ramos Paula S PS Marion Miranda C MC Ryan Mary M Tsoras Monica M Weiler Tracey T Wagner Michael M Keddache Mehdi M Haas J Peter JP Mueller Cornelia C Prahalad Sampath S Bohnsack John J Wise Carol A CA Punaro Marilynn M Zhang Dongping D Rosé Carlos D CD Comeau Mary E ME Divers Jasmin J Glass David N DN Langefeld Carl D CD

Arthritis and rheumatism 20101101 11

<h4>Objective</h4>To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA).<h4>Methods</h4>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 ...[more]

PMID: 20722033

Similar Datasets

Project description:ObjectiveSubtypes 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.MethodsCases 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.ResultsThe 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.ConclusionWe 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.

Project description:Juvenile idiopathic arthritis (JIA) is an autoimmune disease that is characterized by persistent chronic arthritis and affected by genetic and environmental factors. Different genetic variations have been reported as risk factors for JIA. However, given that many results could not be replicated in individuals of different ancestral origin, it was assumed that heterogeneous genetic factors are involved in this disease. In the present study, we analyzed three single nucleotide polymorphisms (SNPs), namely PTPRC (rs10919563), TYK2 (rs34536443) and PRKCQ (rs4750316), which were found to be associated with JIA in previous studies. We also investigated whether the intron?4 located 27?bp VNTR of endothelial nitric oxide synthase (eNOS), is associated with risk for JIA in Greece. In total, 125 JIA patients and 221 healthy controls from northern Greece were included in the study as a sample set. Samples were then analyzed, and genotyped for the three SNPs with TaqMan primer?probe sets, using a Real?Time PCR platform (ViiA™ 7 Real?Time PCR system), while eNOS VNTR polymorphism was genotyped by PCR. Statistical analysis was performed using a GraphPad Prism statistical program. The ?2 test was used to examine differences of genotype and allele frequencies between patients and controls. Statistical significance was defined by using the two?tailed P<0.05 test. Bioinformatics analysis was conducted by using BlastP, Pymol, Maestro and Desmond. In the case?control association study performed, eNOS only was found to be associated with JIA. Genotype a/a and allele 'a' were found in a higher frequency in JIA patients than in controls [p<0.0001, odds ratio (OR)=0.15, 95% confidence intervals (CI): 0.065?0.37; and p<0.0001, OR=0.34, 95% CI: 0.23?0.49, respectively]. No associations with JIA were detected for TYK2, PTPRC or PRKCQ. Aiming to investigate the structural consequences and the structure/function relationships accompanying the Pro1104 to Ala (rs34536443) mutation on TYK2 protein, bioinformatics analysis was performed. Combining three?dimensional (3D)?modeling and molecular dynamics simulations we identified changes in structural flexibility, affecting the functionality of the kinase domain of TYK2. To the best of our knowledge, this is the first time that eNOS VNTR polymorphism is associated with susceptibility to JIA, suggesting a differential role of allele 'a' in various complex diseases. The current data emphasize the importance of comparative studies in populations of a different ancestral background towards the clarification of the role of specific alleles in the development of JIA.

Project description:OBJECTIVE:Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes. METHODS:Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis. RESULTS:Meta-analysis showed evidence of association (P < 1 × 10-6 ) at 9 regions: PRR9_LOR (P = 5.12 × 10-8 ), ILDR1_CD86 (P = 6.73 × 10-8 ), WDFY4 (P = 1.79 × 10-7 ), PTH1R (P = 1.87 × 10-7 ), RNF215 (P = 3.09 × 10-7 ), AHI1_LINC00271 (P = 3.48 × 10-7 ), JAK1 (P = 4.18 × 10-7 ), LINC00951 (P = 5.80 × 10-7 ), and HBP1 (P = 7.29 × 10-7 ). Of these, PRR9_LOR, ILDR1_CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22. CONCLUSION:This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA.

Project description:BACKGROUND:Many autoimmune diseases share common pathogenic mechanisms, cytokine pathways and systemic inflammatory cascades; however, large studies quantifying the co-existence of autoimmune diseases in patients with juvenile idiopathic arthritis (JIA) have not been conducted. METHODS:We performed a cross-sectional study using two United States administrative healthcare claims databases (Truven Health MarketScan® Commercial Database and IMS PharMetrics database) to screen for the prevalence of multiple autoimmune diseases in patients with JIA and in a control group with attention deficit hyperactivity disorder (ADHD). Patients with a diagnosis code for JIA or ADHD between January 1, 2006 and September 30, 2017 were separated into two age cohorts (<?18 and???18?years) and matched (maximum 1:5) based on age, sex, number of medical encounters, and calendar year of diagnosis. The prevalence rates of 30 pre-specified autoimmune diseases during the 12-month periods before and after diagnosis were compared. RESULTS:Overall, 29,215 patients with JIA and 134,625 matched control patients with ADHD were evaluated. Among patients in the MarketScan database, 28/30 autoimmune diseases were more prevalent in patients with JIA aged <?18?years and 29/30 were more prevalent in patients aged ? 18?years when compared with a matched cohort of patients with ADHD. In the PharMetrics database, 29/30 and 30/30 autoimmune diseases were more prevalent in patients with JIA aged <?18 and???18?years, respectively, compared with a matched cohort of patients with ADHD. Among patients with JIA aged <?18?years, the greatest odds ratios (ORs) were seen for Sjögren's syndrome/sicca syndrome and uveitis. Among patients aged ? 18?years in the MarketScan database, the greatest ORs were recorded for uveitis. Data from the PharMetrics database indicated that the greatest ORs were for uveitis and chronic glomerulonephritis. CONCLUSIONS:Patients with JIA are more likely to have concurrent autoimmune diseases than matched patients with ADHD. Having an awareness of the co-existence of autoimmune diseases among patients with JIA may play an important role in patient management, treatment decisions, and outcomes. TRIAL REGISTRATION:Not applicable.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets