Independent confirmation of juvenile idiopathic arthritis genetic risk loci previously identified by immunochip array analysis.
Ontology highlight
ABSTRACT:
SUBMITTER: Chiaroni-Clarke RC
PROVIDER: S-EPMC4276094 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Publications
Independent confirmation of juvenile idiopathic arthritis genetic risk loci previously identified by immunochip array analysis.
Chiaroni-Clarke Rachel C RC Munro Jane E JE Chavez Raul A RA Pezic Angela A Allen Roger C RC Akikusa Jonathan D JD Piper Susan E SE Saffery Richard R Ponsonby Anne-Louise AL Ellis Justine A JA
Pediatric rheumatology online journal 20141216
<h4>Background</h4>Our understanding of the genetic factors underlying juvenile idiopathic arthritis (JIA) is growing, but remains incomplete. Recently, a number of novel genetic loci were reported to be associated with JIA at (or near) genome-wide significance in a large case-control discovery sample using the Immunochip genotyping array. However, independent replication of findings has yet to be performed. We therefore attempted to replicate these newly identified loci in the Australian CLARIT ...[more]
Similar Datasets
Project description:BACKGROUND: Over the last five years, there have been numerous reports of association of juvenile idiopathic arthritis with single nucleotide polymorphisms (SNPs) at various loci outside the major histocompatibility complex (MHC) region. However, the majority of these association findings have been generated using a limited number of international cohorts, and thus there is benefit in further independent replication. To address this, we examined a total of 56 SNPs in 42 non-MHC gene regions previously reported to be associated with JIA, in the ChiLdhood Arthritis Risk factor Identification sTudY (CLARITY), a new Australian collection of cases and healthy child controls. FINDINGS: Genotyping was performed on a total of 324 JIA cases (mean age 9.7 years, 67.3% female) and 568 controls (mean age 7.8 years, 40.7% female). We demonstrated clear evidence for replication of association of JIA with SNPs in or around c12orf30, c3orf1, PTPN22, STAT4, and TRAF1-C5, confirming the involvement of these loci in disease risk. Further, we generated evidence supportive of replication of association of JIA with loci containing AFF3, CD226, MBL2, PSTPIP1, and RANTES (CCL5). These results were robust to sensitivity analyses for ethnicity. CONCLUSION: We have provided valuable independent data as to the underlying genetic architecture of this understudied pediatric autoimmune disease, further confirming five loci outside the MHC, and supporting a role for a further five loci in determining disease risk.
| S-EPMC3606368 | biostudies-literature
Project description:BackgroundGenome-wide association studies (GWAS) have been extremely successful in the search for susceptibility risk factors for complex genetic autoimmune diseases. As more studies are published, evidence is emerging of considerable overlap of loci between these diseases. In juvenile idiopathic arthritis (JIA), another complex genetic autoimmune disease, the strategy of using information from autoimmune disease GWAS or candidate gene studies to help in the search for novel JIA susceptibility loci has been successful, with confirmed association with two genes, PTPN22 and IL2RA. Rheumatoid arthritis (RA) is an autoimmune disease that shares similar clinical and pathological features with JIA and, therefore, recently identified confirmed RA susceptibility loci are also excellent JIA candidate loci.ObjectiveTo determine the overlap of disease susceptibility loci for RA and JIA.Methods/st> Fifteen single nucleotide polymorphisms (SNPs) at nine RA-associated loci were genotyped in Caucasian patients with JIA (n=1054) and controls (n=3531) and tested for association with JIA. Allele and genotype frequencies were compared between cases and controls using the genetic analysis software, PLINK.ResultsTwo JIA susceptibility loci were identified, one of which was a novel JIA association (STAT4) and the second confirmed previously published associations of the TRAF1/C5 locus with JIA. Weak evidence of association of JIA with three additional loci (Chr6q23, KIF5A and PRKCQ) was also obtained, which warrants further investigation.ConclusionAll these loci are good candidates in view of the known pathogenesis of JIA, as genes within these regions (TRAF1, STAT4, TNFAIP3, PRKCQ) are known to be involved in T-cell receptor signalling or activation pathways.
| S-EPMC2935325 | biostudies-literature
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.
| S-EPMC5779956 | biostudies-literature
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.
| S-EPMC5874801 | biostudies-literature
Project description:ObjectivesRheumatoid arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA); indeed, the strategy of investigating whether RA susceptibility loci also confer susceptibility to JIA has already proved highly successful in identifying novel JIA loci. A plethora of newly validated RA loci has been reported in the past year. Therefore, the aim of this study was to investigate these single nucleotide polymorphisms (SNP) to determine if they were also associated with JIA.MethodsThirty-four SNP that showed validated association with RA and had not been investigated previously in the UK JIA cohort were genotyped in JIA cases (n=1242), healthy controls (n=4281), and data were extracted for approximately 5380 UK Caucasian controls from the Wellcome Trust Case-Control Consortium 2. Genotype and allele frequencies were compared between cases with JIA and controls using PLINK. A replication cohort of 813 JIA cases and 3058 controls from the USA was available for validation of any significant findings.ResultsThirteen SNP showed significant association (p<0.05) with JIA and for all but one the direction of association was the same as in RA. Of the eight loci that were tested, three showed significant association in the US cohort.ConclusionsA novel JIA susceptibility locus was identified, CD247, which represents another JIA susceptibility gene whose protein product is important in T-cell activation and signalling. The authors have also confirmed association of the PTPN2 and IL2RA genes with JIA, both reaching genome-wide significance in the combined analysis.
| S-EPMC3375583 | biostudies-literature
Project description:Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management.
| S-EPMC4848803 | biostudies-other
Project description:Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children which could cause severe disability. Genomic studies have discovered substantial number of risk loci for JIA, however, the mechanism of how these loci affect JIA development is not fully understood. Neutrophil is an important cell type involved in autoimmune diseases. To better understand the biological function of genetic loci in neutrophils during JIA development, we took an integrated multi-omics approach to identify target genes at JIA risk loci in neutrophils and constructed a protein-protein interaction network via a machine learning approach. We identified genes likely to be JIA risk loci targeted genes in neutrophils which could contribute to JIA development.
| S-EPMC6445851 | biostudies-literature
Project description:To describe recent evidence from the literature pertaining to juvenile idiopathic arthritis (JIA)-associated uveitis.Uveitis is most common in extended oligoarticular JIA. A significant number of patients already have ocular complications at time of diagnosis of uveitis. Risk factors for complications include either abnormally high or low intraocular pressure, posterior synechiae, male sex, temporal proximity to diagnosis of arthritis and topical corticosteroid use. Use of immunosuppressive agents significantly reduces ocular complications. Aggressive perioperative control of intraocular inflammation is necessary for successful cataract surgery with lens implantation. Controlled clinical trials are under way to assess the efficacy of biologic agents in JIA-associated uveitis. Long-term safety, however, is still unknown.JIA-associated uveitis carries significant ocular morbidity that lasts well into adulthood. Treatment with immunosuppressive agents can reduce the risk of ocular complications. Biologic agents hold promise in the treatment of JIA-associated uveitis, but require long-term data to assess their safety.
| S-EPMC3089768 | biostudies-literature
Project description:Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease. The development of associated uveitis represents a significant risk for serious complications, including permanent loss of vision. Initiation of early treatment is important for controlling JIA-uveitis, but the disease can appear asymptomatically, making frequent screening procedures necessary for patients at risk. As our understanding of pathogenic drivers is currently incomplete, it is difficult to assess which JIA patients are at risk of developing uveitis. Identification of specific risk factors for JIA-associated uveitis is an important field of research, and in this review, we highlight the genomic, transcriptomic, and proteomic factors identified as potential uveitis risk factors in JIA, and discuss therapeutic strategies.
| S-EPMC8393258 | biostudies-literature
Project description:BackgroundHaptoglobin (Hp), a liver derived acute phase inflammatory protein (APP), has scarcely been studied in juvenile idiopathic arthritis (JIA). Hp can occur in blood as two isoforms (Hp1 and Hp2) in precursor and mature forms. Routine clinical chemistry immunoturbidimetry does not discern these forms. It is unknown how different forms relate to disease activity in JIA. Our aims were to determine allele frequency and plasma concentrations of different Hp forms at higher versus lower JIA disease activity and compare to other APPs.MethodsPlasma from JIA (n = 77) and healthy (n = 42) children were analyzed for apparent Hp allelic frequency and densitometric concentrations of alpha forms by Western blot (WB). Polymerase chain reaction (PCR) (buffy coat) was performed in a subset to estimate conformity with genetics. At higher versus lower juvenile arthritis disease activity score (JADAS27) (which includes erythrocyte sedimentation rate (ESR)), total mature Hp concentration from WB was compared and correlated against immunoturbidimetry and total protein, albumin, serum amyloid A (SAA) and C-reactive protein (CRP).ResultsAt 300-fold dilution needed to study mature forms in Western blot, precursors were undetectable. Hp2 contributed most signal in most samples. Hp allele frequency was similar in JIA and controls. Both mature forms, taken separately or by sum, declined following treatment, but remained above concentrations of healthy controls, even in a remission subset that achieved JADAS27 < 1. Densitometry correlated with immunoturbidimetry. Hp concentrations correlated with JADAS27, albumin (negatively), CRP and SAA with immunoturbidimetric method correlating strongest to JADAS27 (Spearman R ~ 0.6, p < 0.0001).ConclusionHp allele frequency in JIA is similar to the general population, indicating that children with JIA should have the same possibility as in healthy children to produce preHp2 (zonulin), thought to increase intestinal permeability. Circulating Hp concentrations largely parallel other APPs and ESR; none of these measures correlate very strongly to JADAS27 score but Hp can be measured from capillary sampling which is impossible with ESR.
| S-EPMC9753416 | biostudies-literature