Risk Of Juvenile Idiopathic Arthritis Research Articles

Incidence and genetic risk of juvenile idiopathic arthritis in Norway by latitude.

We aimed to investigate the incidence of juvenile idiopathic arthritis (JIA) in the three geographical regions of Norway, and whether potential regional incidence differences are explained by environmental or genetic factors across regions. We conducted a register-based cohort study including all Norwegian children born 2004-2019, with follow-up throughout 2020. The JIA diagnosis defined by ≥ 2 ICD-10 codes for JIA was validated against medical records. The incidence rate (IR) and hazard ratio (HR) for JIA were estimated for all Norway, and for the regions North, Mid, and South. In a sub-sample from the Norwegian Mother, Father, and Child Cohort Study (MoBa), the genetic risk for JIA was assessed in the three regions. After median 9.1 (range 0.3-16.0) years of follow-up, we identified 1184 JIA cases and 910058 controls. The IR for JIA/100 000 person-years was 14.4 in all of Norway; 25.9 in region North, 17.9 in region Mid and 12.5 in region South. The HR (95% CI) of JIA in region North was 2.07 (1.77-2.43) and in region Mid 1.43 (1.23-1.67) compared to region South. Adjustments for perinatal factors, socioeconomic status, and early antibiotic exposure did not change our estimates substantially. In MoBa (238 cases, 57392 controls), the association between JIA and region of birth was no longer significant when adjusting for genetic factors. We found a higher incidence of JIA with increasing latitude, without evidence for available environmental factors explaining the observed gradient. In contrast, genetic factors modified the association, but further studies are warranted.

Causal effect of gut microbiota on juvenile idiopathic arthritis: A two-sample Mendelian a randomization study.

There is increasing evidence of a significant association between the gut microbiome and juvenile idiopathic arthritis (JIA). However, whether this association is causal remains to be determined. This study was a two-sample Mendelian randomization (MR) study using publicly available genome-wide association study (GWAS) summary data to investigate the causal relationship between the gut microbiome and JIA. We used summary data on gut flora and JIA obtained from genome-wide association studies (GWAS) from MiBioGen and NHGRI-EBI, using inverse variance weighting as the main method to analyse causality in the TSMR causality analysis. To check the stability of the TSMR results, we performed several sensitivity analyses and assessed the presence of reverse causality through a reverse TSMR analysis. We calculated the degree of sample overlap where applicable. The current TSMR analyses identified four bacterial taxa associated with JIA. Specifically, two bacteria, Catenibacterium (p = 2 × 10-2) and Holdemania (p = 4 × 10-2), were negatively associated with the risk of developing JIA, suggesting a protective effect, while Olsenella (p = 1 × 10-2) and Rikenellaceae (RC9gutgroup) (p = 1 × 10-2) were positively associated with the risk of JIA, suggesting that these two bacteria may be risk factors for JIA. However, the results for Catenibacterium and Holdemania should be interpreted with caution due to instability observed in 'leave-one-out' sensitivity analyses. Reverse TSMR analyses found no evidence of reverse causality between JIA and gut flora. Our confirmation of a causal relationship between gut flora and JIA provides an innovative perspective for the study of JIA: targeting and modulating dysregulation of specific bacterial taxa to prevent and treat JIA.

Using Functional Genomic Data in Monocytes/Macrophages and Genotyping to Nominate Disease-Driving Single Nucleotide Polymorphisms and Target Genes in Juvenile Idiopathic Arthritis.

GWAS have identified multiple regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single nucleotide polymorphisms (SNPs) that drive disease risk is impeded by the SNPs' that identify risk loci being in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and use genetic information to inform patient care. We used genotyping and functional data in primary human monocytes/macrophages to nominate disease-driving SNPs on JIA risk haplotypes and identify their likely target genes. We identified JIA risk haplotypes using Immunochip data from Hinks et al (Nature Gen 2013) and the meta-analysis from McIntosh et al (Arthritis Rheum 2017). We used genotyping data from 3,939 children with JIA and 14,412 healthy controls to identify SNPs that: (1) were situated within open chromatin in multiple immune cell types and (2) were more common in children with JIA than the controls (p< 0.05). We intersected the chosen SNPs (n=846) with regions of bi-directional transcription initiation characteristic of non-coding regulatory regions detected using dREG to analyze GRO-seq data. Finally, we used MicroC data to identify gene promoters interacting with the regulatory regions harboring the candidate causal SNPs. We identified 190 SNPs that overlap with dREG peaks in monocytes and126 SNPs that overlap with dREG peaks in macrophages. Of these SNPs, 101 were situated within dREG peaks in both monocytes and macrophages, suggesting that these SNPs exert their effects independent of the cellular activation state. MicroC data in monocytes identified 20 genes/transcripts whose promoters interact with the enhancers harboring the SNPs of interest. SNPs in JIA risk regions that are candidate causal variants can be further screened using functional data such as GRO-seq. This process identifies a finite number of candidate causal SNPs, the majority of which are likely to exert their biological effects independent of cellular activation state in monocytes. Three-dimensional chromatin data generated with MicroC identifies genes likely to be influenced by these SNPs. These studies demonstrate the importance of investigations into the role of innate immunity in JIA.

Causal association of juvenile idiopathic arthritis or JIA-associated uveitis and gut microbiota: a bidirectional two-sample Mendelian randomisation study.

The gut microbiota significantly influences the onset and progression of juvenile idiopathic arthritis (JIA) and associated uveitis (JIAU); however, the causality remains unclear. This study aims to establish a causal link between gut microbiota and JIA or JIAU. Using publicly available genome-wide association studies (GAWS) summary data, we conducted a two-sample Mendelian randomisation (MR) analysis employing various methods, namely inverse variance weighted (IVW), simple mode, weighted mode, weighted median and MR-Egger regression methods, to assess the causal association between JIA or JIAU and gut microbiota. Sensitivity analyses, including Cochrane's Q test, MR-Egger intercept test, leave-one-out analysis and MR-PRESSO, were performed to evaluate the robustness of the MR results. Subsequently, reverse MR analysis was conducted to determine causality between gene-predicted gut microbiota abundance and JIA or JIAU. The MR analysis revealed a causal association between gut microbiota abundance variations and JIA or JIAU risk. Specifically, the increased abundance of genus Ruminococcaceae UCG013 (OR: 0.055, 95%CI: 0.006-0.103, p = 0.026) and genus Ruminococcaceae UCG003 (β: 0.06, 95%CI: 0.003-0.117, p = 0.041) correlated with an increased risk of JIA, while genus Lachnospiraceae UCG001 (OR: 0.833, 95%CI: 0.699~0.993, p = 0.042) was associated with a reduced risk of JIA, among others. Sensitivity analysis confirmed MR analysis robustness. This study provides substantial evidence supporting a causal association between genetically predicted gut microbiota and JIA or JIAU. It highlights the significant role of intestinal flora in JIA or JIAU development, suggesting their potential as novel biomarkers for diagnosis and prevention. These findings offer valuable insights to mitigate the impact of JIA or JIAU.

A systematic strategy for identifying causal single nucleotide polymorphisms and their target genes on Juvenile arthritis risk haplotypes

BackgroundAlthough genome-wide association studies (GWAS) have identified multiple regions conferring genetic risk for juvenile idiopathic arthritis (JIA), we are still faced with the task of identifying the single nucleotide polymorphisms (SNPs) on the disease haplotypes that exert the biological effects that confer risk. Until we identify the risk-driving variants, identifying the genes influenced by these variants, and therefore translating genetic information to improved clinical care, will remain an insurmountable task. We used a function-based approach for identifying causal variant candidates and the target genes on JIA risk haplotypes.MethodsWe used a massively parallel reporter assay (MPRA) in myeloid K562 cells to query the effects of 5,226 SNPs in non-coding regions on JIA risk haplotypes for their ability to alter gene expression when compared to the common allele. The assay relies on 180 bp oligonucleotide reporters (“oligos”) in which the allele of interest is flanked by its cognate genomic sequence. Barcodes were added randomly by PCR to each oligo to achieve > 20 barcodes per oligo to provide a quantitative read-out of gene expression for each allele. Assays were performed in both unstimulated K562 cells and cells stimulated overnight with interferon gamma (IFNg). As proof of concept, we then used CRISPRi to demonstrate the feasibility of identifying the genes regulated by enhancers harboring expression-altering SNPs.ResultsWe identified 553 expression-altering SNPs in unstimulated K562 cells and an additional 490 in cells stimulated with IFNg. We further filtered the SNPs to identify those plausibly situated within functional chromatin, using open chromatin and H3K27ac ChIPseq peaks in unstimulated cells and open chromatin plus H3K4me1 in stimulated cells. These procedures yielded 42 unique SNPs (total = 84) for each set. Using CRISPRi, we demonstrated that enhancers harboring MPRA-screened variants in the TRAF1 and LNPEP/ERAP2 loci regulated multiple genes, suggesting complex influences of disease-driving variants.ConclusionUsing MPRA and CRISPRi, JIA risk haplotypes can be queried to identify plausible candidates for disease-driving variants. Once these candidate variants are identified, target genes can be identified using CRISPRi informed by the 3D chromatin structures that encompass the risk haplotypes.

Relationships among gut microbiota, plasma metabolites, and juvenile idiopathic arthritis: a mediation Mendelian randomization study.

The objective of this study is to investigate the causal relationship between gut microbiota and juvenile idiopathic arthritis, and to identify and quantify the potential role of plasma metabolites as mediators. Using summary-level data from genome-wide association studies, a two-sample Mendelian randomization was conducted involving 131 gut microbiota genus, 1,400 plasma metabolites, and juvenile idiopathic arthritis. Additionally, a two-step approach was employed to quantify the proportion of the effect of gut microbiota on juvenile idiopathic arthritis mediated by plasma metabolites. Effect estimation primarily utilized Inverse Variance Weighting, with further validation using Bayesian weighted Mendelian randomization. In our MR analysis, a positive correlation was observed between Rikenellaceae and the risk of juvenile idiopathic arthritis, while Dorea showed a negative correlation with juvenile idiopathic arthritis risk. Mediation analysis indicated that Furaneol sulfate levels acted as a mediator between Dorea and juvenile idiopathic arthritis, with an indirect effect proportion of 19.94, 95% CI [8.86-31.03%]. Our study confirms a causal relationship between specific microbial genus and juvenile idiopathic arthritis, and computes the proportion of the effect mediated by plasma metabolites, offering novel insights for clinical interventions in juvenile idiopathic arthritis.

Association of Human Papillomavirus Vaccination with Risk for Rheumatoid Arthritis

Introduction: The potential association between Human papillomavirus (HPV) vaccination and the onset of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) remains a pivotal point of exploration in immunization safety discourse. Method: This retrospective cohort study aims to ascertain the risk of RA and JIA following HPV vaccination, utilizing the TriNetX database, tracking the health trajectories of 32,165,650 females, from January 1, 2013, to December 31, 2022. By applying inclusion and exclusion criteria, we formed a balanced cohort of 344,165 HPV-vaccinated individuals, the propensity score-matched 1:1 with unvaccinated controls based on a range of demographic and clinical parameters. This study used the Cox proportional hazards model to analyze the risk of RA and JIA after HPV vaccination, expressed the results by adjusted hazard ratio (aHR) and 95% confidence interval (CI), and used Kaplan-Meier survival analysis. Results: The analysis showed that over a follow-up period of up to 10 years after vaccination, the risks of RA and JIA were significantly reduced in the HPV vaccination group, with aHR of 0.428 (95% CI: 0.372-0.492) and 0.310 (95% CI: 0.262-0.367) respectively. This trend persisted in a sensitivity analysis that replaced the control group with influenza-vaccinated individuals. Subgroup analyses showed that the risk of RA and JIA was significantly reduced in the 9-18 and 19-26 age groups, across ethnic backgrounds, and in the obesity and asthma subgroups, but still among those with a smoking history, the risk reduction was not statistically significant. Conclusion: Our findings highlight the significant protective effect of the HPV vaccine against RA and JIA. Further research is needed to delve deeper into this molecular mechanism.

Etiological Theories of Juvenile Idiopathic Arthritis (JIA): A Narrative Review

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease. It can be classified by diverse clinical presentations across subtypes classified by inflammation, swelling, and pain. This review examines current perspectives on factors impacting JIA etiology and future areas of development. Genetic and environmental factors, including early-life nutrition (i.e. breastmilk), mode of infant delivery, antibiotic exposure, and infections have been proposed as etiological candidates in the literature. Various human leukocyte antigen (HLA) genes and non-HLA genes related to immune signaling are risk factors for specific JIA subtypes. The impact of infection on JIA development has also been examined; it remains unclear whether infection plays a protective or harmful role. Moreover, shorter durations of breastfeeding during childhood may be associated with an increased risk of JIA development, given that breast milk consumption favorably increases bifidobacterium, changes the composition of the microbiome, and increases microbial diversity. Additionally, mode of delivery can play a role in the onset of JIA as birth delivery through Cesarean section puts children at a higher risk of JIA compared to infants born vaginally. Lastly, antibiotic exposure and its dose- and timedependent relationship also play a role in the microbiome and JIA pathogenesis. This research is significant, as an increased understanding of the etiology of clinically heterogeneous JIA subtypes may improve future treatments. Current limitations, research gaps, and future directions in the field are also discussed.

Роль вітаміну D при ювенільному ідіопатичному артриті

Considering the role of vitamin D in mineral metabolism and its extracellular effects, including immunomodulation with a tendency to suppress the immune response, there is significant interest in determining its role in developing autoimmune diseases, including juvenile idiopathic arthritis (JIA). Purpose - to determine the role of vitamin D in the development and course of JIA based on a systematic analysis of literature sources over the last 7 years. A search was conducted on PubMed for articles on the role of vitamin D in the development and course of JIA, using combinations of the following terms: “vitamin D” and “juvenile idiopathic arthritis”. The review included scientific publications with available full texts published from January 2017 to August 2023. The analysis results showed significant variations in the level of 25(OH)D among patients with JIA, and the vitamin D status in the majority of JIA patients was not optimal. However, the percentage of patients with suboptimal levels and vitamin D deficiency, according to the majority of studies, was not more significant than in the general population. Nevertheless, a correlation was found between low 25(OH)D concentration and high activity of JIA. Additional vitamin D supplementation did not impact the reduction of JIA activity or the improvement of indicators of bone mineral density. However, some publications emphasize the positive effect of sun exposure in reducing the risk of JIA. Further research is needed to clarify the necessity of additional vitamin D supplementation involving a larger number of patients, standardization, selection of optimal doses, and treatment duration. No conflict of interests was declared by the authors.

Inflammatory arthritis and eye diseases: a Mendelian randomization study.

The aim of this study was to determine causal associations between inflammatory arthritis and eye diseases (disorders of sclera, cornea, iris, and ciliary body [DSCIC] and disorders of choroid and retina [DCR]). Genome-wide association studies' summary data of rheumatoid arthritis (RA) from a large-scale meta-analysis were used to identify genetically predicted RA. UK Biobank source data predicted ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). Furthermore, data from the FinnGen Biobank were used to identify genetically predicted eye diseases. Two-sample Mendelian randomization analysis was used to assess the causal relationship between inflammatory arthritis and eye diseases in the European population. Inverse-variance weighting (IVW) was used as the primary method, while MR-Egger, weighted median, and MR-PRESSO outlier test were used to detect heterogeneity and pleiotropy. Genetically determined RA was indeed observed to have a causal effect on DSCIC (odds ratio [OR] = 1.084, p = 2.353 × 10-10) and DCR (OR = 1.151, p = 1.584 × 10-19). AS was causally associated with DSCIC (OR = 1.068, p < 2.024 × 10-8). In addition, PsA was also found to have a causal association with an increased risk of 17.9% for the development of DSCIC (OR = 1.179, p = 0.003). On the flip side, DSCIC increased the risk of JIA (OR = 2.276, p = 0.003). Our study provided genetic evidence for the causal associations of RA, AS, and PsA with an increased risk of DSCIC, and a causal association between RA and DCR was also identified. In addition, DSCIC greatly increased the risk of JIA.

IL12B and IL17 genes polymorphisms associated with differential susceptibility to juvenile idiopathic arthritis and juvenile-onset systemic lupus erythematosus in Chinese children

Genetic factors play a crucial role in the immune response of juvenile idiopathic arthritis (JIA) and juvenile-onset systemic lupus erythematosus (JSLE). This study aimed to investigate the association of IL12B (rs3212227, rs6887695) and IL17 (rs2275913, rs763780) gene polymorphisms with the susceptibility of JIA and JSLE in Chinese children. A total of 303 healthy controls and 304 patients including 160 JIA and 144 patients were analyzed, and the genetic polymorphisms were genotyped by using a Sequenom MassArray system. There was a significant association between the IL12B rs3212227 genotype and the increased risk of JSLE (P = .01). For rs6887695, the minor allele C was significantly associated with the increased risk of JIA (odds ratio = 1.48, 95% confidence interval [CI] = 1.12–1.95, P = .005). Moreover, rs6887695 genotype was significantly associated with both JIA and JSLE susceptibility (P &lt; .05). Besides, IL12B haplotype GC significantly associated with the increased risk of JIA (P = .016). However, no significant difference was found between the IL17 (rs2275913, rs763780) gene polymorphisms and JIA or JSLE susceptibility (P &gt; .05). And similar genotype distributions of IL12B and IL17 polymorphisms were found between the patients with nephritis and without nephritis in JSLE (P &gt; .05). Our results indicated that IL12B polymorphisms was associated with an increased risk for the development of JIA and JSLE in Chinese children, highlighting the involvement of inflammation in the pathogenesis of JIA and JSLE. Moreover, there was a risk haplotype in IL12B which could increase the risk of JIA.

Antibiotic exposure in prenatal and early life and risk of juvenile idiopathic arthritis: a nationwide register-based cohort study

ObjectivesEarly antibiotic exposure influences the gut microbiota which is believed to be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). We aimed to investigate the association between systemic antibiotics...

A systematic review and meta-analysis of environmental factors associated with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease, thought to be influenced by both genetics and the environment. Identifying environmental factors associated with disease risk will improve knowledge of disease mechanisms and ultimately benefit patients. This review aimed to collate and synthesize the current evidence of environmental factors associated with JIA. MEDLINE (Ovid), EMBASE (Ovid), Cumulative Index of Nursing and Related Health Literature (EBSCOhost), science network (WOS, Clarivate Analytics), Chinese National Knowledge Infrastructure, and Chinese Biological Medical Database were systematically searched. Study quality was rated using the Newcastle-Ottawa Scale. Pooled estimates for each environmental factor were generated using a random-effects, inverse-variance method, where possible. The remaining environmental factors were synthesized in narrative form. This review includes environmental factors from 23 studies (6 cohorts and 17 case-control studies). Cesarean section delivery was associated with increased JIA risk (pooled relative risk [RR] 1.103, 95% CI 1.033-1.177). Conversely, maternal smoking of more than 20 cigarettes/day (pooled RR 0.650, 95% CI 0.431-0.981) and gestational smoking (pooled RR0.634, 95% CI 0.452-0.890) were associated with decreased JIA risk. This review identifies several environmental factors associated with JIA and demonstrates the huge breadth of environmental research. We also highlight the challenges of combining data collected over this period due to limited study comparability, evolution in healthcare and social practices, and changing environment, which warrant consideration when planning future studies.

Juvenile idiopathic arthritis-associated genetic loci exhibit spatially constrained gene regulatory effects across multiple tissues and immune cell types

Juvenile idiopathic arthritis (JIA) is an autoimmune, inflammatory joint disease with complex genetic etiology. Previous GWAS have found many genetic loci associated with JIA. However, the biological mechanism behind JIA remains unknown mainly because most risk loci are located in non-coding genetic regions. Interestingly, increasing evidence has found that regulatory elements in the non-coding regions can regulate the expression of distant target genes through spatial (physical) interactions. Here, we used information on the 3D genome organization (Hi-C data) to identify target genes that physically interact with SNPs within JIA risk loci. Subsequent analysis of these SNP-gene pairs using data from tissue and immune cell type-specific expression quantitative trait loci (eQTL) databases allowed the identification of risk loci that regulate the expression of their target genes. In total, we identified 59 JIA-risk loci that regulate the expression of 210 target genes across diverse tissues and immune cell types. Functional annotation of spatial eQTLs within JIA risk loci identified significant overlap with gene regulatory elements (i.e., enhancers and transcription factor binding sites). We found target genes involved in immune-related pathways such as antigen processing and presentation (e.g., ERAP2, HLA class I and II), the release of pro-inflammatory cytokines (e.g., LTBR, TYK2), proliferation and differentiation of specific immune cell types (e.g., AURKA in Th17 cells), and genes involved in physiological mechanisms related to pathological joint inflammation (e.g., LRG1 in arteries). Notably, many of the tissues where JIA-risk loci act as spatial eQTLs are not classically considered central to JIA pathology. Overall, our findings highlight the potential tissue and immune cell type-specific regulatory changes contributing to JIA pathogenesis. Future integration of our data with clinical studies can contribute to the development of improved JIA therapy.

PADI4 and IL-33 gene polymorphisms with susceptibility to systemic lupus erythematosus and juvenile idiopathic arthritis, a systematic review and meta-analysis.

This study evaluated the association between peptidyl arginine deiminase type IV (PADI4) and interleukin 33 (IL-33) with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA). We searched the PubMed, Web of Science, Embase and Cochrane Library databases to retrieve articles published up to January 20, 2023. Stata/SE 17.0 (College Station, TX) software was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). The cohort study, case-control study focusing on the PADI4, IL-33 polymorphism, and SLE, JIA were retrieved. The data included basic information of each study and the genotypes and allele frequencies. Studies in PADI4 rs2240340 = 2 and 3 IL-33(rs1891385 = 3, rs10975498 = 2, rs1929992 = 4) were found in 6 articles. Overall, only the IL-33 rs1891385 show significant association between SLE in all 5 models. The results were OR (95% CI) = 1.528 (1.312, 1.778), P = .000 in Allele model (C vs A), OR (95% CI) =1.473 (1.092, 1.988), P = .000 in Dominant model (CC + CA vs AA), 2.302 (1.583, 3.349), P = .000 in Recessive model (CC vs CA + AA), 2.711 (1.845, 3.983), P = .000 in Homozygote model (CC vs AA), 5.568 (3.943, 7.863), P = .000 in Heterozygote model (CA vs AA). PADI4 rs2240340, IL-33 rs10975498, IL-33 rs1929992 were not found to be association with the risk of SLE and JIA. In gene model, statistically significant association was found between IL-33 rs1891385 and SLE in sensitivity analysis. Egger's publication bias plot showed there was no publication bias (P = .165). Only in recessive model the heterogeneity test was significant (I2 = 57.9%, P ≤ .093) of IL-33 rs1891385. The current study suggests that in all 5 model, IL-33 rs1891385 polymorphism may be associated with genetic susceptibility to SLE. There was unclear association found between PADI4 rs2240340, IL-33 rs10975498, and IL-33 rs1929992 polymorphisms and SLE and JIA. Due to the limitations of included studies and the risk of heterogeneity, additional research is required to confirm our findings. CRD42023391268.

Juvenile idiopathic arthritis in children and adolescents with atopic dermatitis: A Finnish nationwide registry study

Juvenile idiopathic arthritis in children and adolescents with atopic dermatitis: A Finnish nationwide registry study

Ассоциации гена VDR с клиническими проявлениями, осложнениями и обеспеченностью витамином D на фоне ювенильного идиопатического артрита у детей

Objective. To conduct an association search between genetic variants (c.1206T&gt;C, c.152T&gt;C, c.1174+283G&gt;A) of the VDR gene and clinical manifestations of juvenile idiopathic arthritis (JIA), need for genetically engineered biological drugs (GEBDs) and vitamin D status in children. Patients and methods. This study included 150 children (mean age: 9.11 ± 2.21 years) with JIA and 333 healthy controls. The determination of serum calcidiol concentrations was performed in all patients. Polymorphic variants of the VDR gene (c.1206T&gt;C, c.1175-9G&gt;T, c.152T&gt;C, c.1174+283G&gt;A) were tested by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) technique. Results. Carriers of the minor TT genotype of the genetic variant c.1206T&gt;C(A&gt;G) TaqI are 4 time more likely to develop systemic JIA, 5 time more likely to have high disease activity and uveitis, as well as 9.9 times more often require prescription of GEBDs. Carriers of the minor genotype TT of the genetic variant c.152T&gt;C FokI are 7.7 times more likely to develop systemic JIA and 4.3 times – polyarticular JIA, 6.2 times more likely to have high disease activity and 5.6 times – uveitis, 8 times more often have a severe calcidiol deficiency and 4 times more often require prescription of GEBDs. Carrying the minor AA genotype of the BsmlI polymorphism (c.1174+283G&gt;A) increases the risk of systemic-onset JIA by 17 times, high disease activity and uveitis – by 18 times, and need for GEBDs – by 15 times; carrying the AA and GA genotypes increases the risk of calcidiol deficiency by 5 times and severe calcidiol deficiency by 9 times. Conclusion. All studied genetic variants of the VDR gene verifiably affect the development of clinical manifestations, complications, calcidiol levels and response to therapy in JIA. Key words: VDR gene, juvenile idiopathic arthritis, children, vitamin D, autoimmune disease

PADI4 and IL-33 gene polymorphisms associated with differential susceptibility to juvenile-onset systemic lupus erythematosus and juvenile idiopathic arthritis in Chinese children

Juvenile systemic lupus erythematosus (JSLE) and juvenile idiopathic arthritis (JIA) are two common types of autoimmune diseases in children with unclear pathogenesis. Both peptidyl arginine deiminase type IV (PADI4) and interleukin 33 (IL-33) are the key molecular involved in immune responses in autoimmune diseases. Usually, it may share the same risk genetic alleles for autoimmune diseases. So measurement of PADI4 and IL-33 polymorphisms was conducted with 303 healthy controls, 144 JSLE patients and 160 JIA patients in this study. It demonstrated that there was a significant association between PADI4 genotypes (rs2240340: CT, CT + CC), IL-33 genotype (rs1929992: TT) and JSLE susceptibility in Southwest China population. While no significant association with the risk of JIA were observed no matter at allelic or genotypic levels. Our study reveals the importance of PADI4 and IL-33 polymorphisms with JSLE risk and their roles in the development of the diseases need more further researches.

Impact of Kawasaki disease on juvenile idiopathic arthritis in real-world patients: A population-based cohort study.

Recent research has demonstrated the commonality of several biological markers between Kawasaki disease (KD) and juvenile idiopathic arthritis (JIA), including interleukin-1β and -6. Therefore, in this cohort study, we assessed whether KD increases the risk of JIA. This study enrolled 7009 patients with and 56 072 individuals without KD in the period 2010-2018 from Taiwan's National Health Insurance Research Database. On the basis of sex, age, and comorbidities, we executed propensity score matching at the ratio 1:8. The adjusted hazard ratio (aHR) for JIA was determined through multiple Cox regression. Stratified analysis and sensitivity tests were also employed. When adjusting for age, sex, and comorbidities, the JIA risk was noted to be 2.02-fold greater in children with KD than it was in those without (aHR: 2.02, 95% confidence interval: 1.12-3.67, p = 0.0205). The sensitivity test and subgroup analysis obtained consistent findings in the different sex and comorbidity subgroups. Children's risk of JIA is higher if they have KD. Pediatricians should consider the possibility of JIA in this population. More investigations are necessary to identify the pathological mechanisms that link JIA and KD.

Vitamin D Levels and Risk of Juvenile Idiopathic Arthritis: A Mendelian Randomization Study.

Observational studies report mixed findings regarding the association between vitamin D and juvenile idiopathic arthritis (JIA) incidence or activity; however, such studies are susceptible to considerable bias. Because low vitamin D levels are common within the general population and easily corrected, there is potential public health benefit in identifying a causal association between vitamin D insufficiency and JIA incidence. To limit bias due to confounding and reverse causation, we examined the causal effect of the major circulating form of vitamin D, 25-hydroxy vitamin D (25-[OH]D), on JIA incidence using Mendelian randomization (MR). In this 2-sample MR analysis, we used summary level data from the largest and most recent genome-wide association study of 25-(OH)D levels (sample size 443,734), alongside summary data from 2 JIA genetic studies (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to pleiotropy, we employed multiple MR methods and sensitivity analyses. We found no evidence of a causal relationship between genetically predicted 25-(OH)D levels and JIA incidence (odds ratio 1.00 [95% confidence interval (95% CI) 0.76, 1.33] per SD increase in standardized natural-log transformed 25-[OH]D levels). This estimate was consistent across all methods tested. Additionally, there was no evidence that genetically predicted JIA causally influences 25-(OH)D levels (-0.002 SD change in standardized natural-log transformed 25-[OH]D levels per doubling odds in genetically predicted JIA [95% CI -0.006, 0.002]). Given the lack of a causal relationship between 25-(OH)D levels and JIA, population level vitamin D supplementation is unlikely to reduce JIA incidence.