Using Chromatin Architecture to Understand the Genetics and Transcriptomics of Juvenile Idiopathic Arthritis.
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ABSTRACT:
SUBMITTER: Kessler H
PROVIDER: S-EPMC6302745 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Using Chromatin Architecture to Understand the Genetics and Transcriptomics of Juvenile Idiopathic Arthritis.
Kessler Haeja H Jiang Kaiyu K Jarvis James N JN
Frontiers in immunology 20181214
The presence of abnormal gene expression signatures is a well-described feature of the oligoarticular and polyarticular forms of juvenile idiopathic arthritis. In this review, we discuss how new insights into genetic risk for JIA and the three dimensional architecture of the genome may be used to develop a better understanding of the mechanisms driving these gene expression patterns. ...[more]
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Project description:BackgroundRheumatoid arthritis and juvenile idiopathic arthritis are two types of autoimmune diseases with inflammation at the joints, occurring to adults and children respectively. There are phenotypic overlaps between these two types of diseases, despite the age difference in patient groups.MethodsTo systematically compare the genetic architecture of them, we conducted analyses at gene and pathway levels and constructed protein-protein-interaction network based on summary statistics of genome-wide association studies of these two diseases. We examined their difference and similarity at each level.ResultsWe observed extensive overlap in significant SNPs and genes at the human leukocyte antigen region. In addition, several SNPs in other regions of the human genome were also significantly associated with both diseases. We found significantly associated genes enriched in 32 pathways shared by both diseases. Excluding genes in the human leukocyte antigen region, significant enrichment is present for pathways like interleukin-27 pathway and NO2-dependent interleukin-12 pathway in natural killer cells.DiscussionThe identification of commonly associated genes and pathways may help in finding population at risk for both diseases, as well as shed light on repositioning and designing drugs for both diseases.
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Project description:Juvenile idiopathic arthritis (JIA) is highly heterogeneous in terms of etiology and clinical presentation with ambiguity in JIA classification. The advance of high-throughput omics technologies in recent years has gained us significant knowledge about the molecular mechanisms of JIA. Besides a minor proportion of JIA cases as monogenic, most JIA cases are polygenic disease caused by autoimmune mechanisms. A number of HLA alleles (including both HLA class I and class II genes), and 23 non-HLA genetic loci have been identified of association with different JIA subtypes. Omics technologies, i.e., transcriptome profiling and epigenomic analysis, contributed significant knowledge on the molecular mechanisms of JIA in addition to the genetic approach. New molecular knowledge on different JIA subtypes enables us to reconsider the JIA classification, but also highlights novel therapeutic targets to develop a cure for the devastating JIA.
| S-EPMC7602566 | biostudies-literature
Project description:OBJECTIVES:Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS:We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS:The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS:The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.
| S-EPMC5530341 | biostudies-literature
Project description:BackgroundThe transcriptomes of peripheral blood cells in children with juvenile idiopathic arthritis (JIA) have distinct transcriptional aberrations that suggest impairment of transcriptional regulation. To gain a better understanding of this phenomenon, we studied known JIA genetic risk loci, the majority of which are located in non-coding regions, where transcription is regulated and coordinated on a genome-wide basis. We examined human neutrophils and CD4 primary T cells to identify genes and functional elements located within those risk loci.MethodsWe analyzed RNA sequencing (RNA-Seq) data, H3K27ac and H3K4me1 chromatin immunoprecipitation-sequencing (ChIP-Seq) data, and previously published chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) data to characterize the chromatin landscapes within the known JIA-associated risk loci.ResultsIn both neutrophils and primary CD4+ T cells, the majority of the JIA-associated linkage disequilibrium (LD) blocks contained H3K27ac and/or H3K4me1 marks. These LD blocks were also binding sites for a small group of transcription factors, particularly in neutrophils. Furthermore, these regions showed abundant intronic and intergenic transcription in neutrophils. In neutrophils, none of the genes that were differentially expressed between untreated patients with JIA and healthy children were located within the JIA-risk LD blocks. In CD4+ T cells, multiple genes, including HLA-DQA1, HLA-DQB2, TRAF1, and IRF1 were associated with the long-distance interacting regions within the LD regions as determined from ChIA-PET data.ConclusionsThese findings suggest that genetic risk contributes to the aberrant transcriptional control observed in JIA. Furthermore, these findings demonstrate the challenges of identifying the actual causal variants within complex genomic/chromatin landscapes.
| S-EPMC5348874 | biostudies-literature
Project description:In juvenile idiopathic arthritis (JIA), there are now more than 25 regions represented by single nucleotide polymorphisms that show strong genetic associations. The causal variants and corresponding functions have not yet been defined for the majority of these regions. Here, we review current JIA association findings and the recent progress in the annotation of noncoding portion of the human genome as well as the new technologies necessary to apply this knowledge to JIA association findings.An international collaboration was able to amass sufficient numbers of JIA and control samples to identify significantly robust genetic associations for JIA. The Encyclopedia of DNA Elements project and the National Institutes of Health (NIH) Roadmap Epigenetics Program have now annotated more than 80% of the noncoding genome, important in understanding the impact of risk loci, the majority of which fall outside of protein coding regions. Recent technological advances in high throughput sequencing, chromatin structure determination, transcription factor and enhancer binding site mapping and genome editing will likely provide a basis for understanding JIA genetic risk.Understanding the role of genetic variation in the cause of JIA will provide insight for disease mechanism and may explain disease heterogeneity between JIA subtypes and between autoimmune diseases in general.
| S-EPMC4445412 | 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: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.
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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.
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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