Susceptibility To Juvenile Idiopathic Arthritis Research Articles

Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWAS) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the power to identify disease-associated loci. SGS analysis identifies genomic segments shared among disease cases that are likely identical by descent and anchored by a disease locus. This approach revealed statistically significant signals for major histocompatibility complex (MHC) class I and class III alleles, particularly HLA-A*02:01, which was observed at a high frequency among cases. Furthermore, we identified an additional risk locus at 12q23.2-23.3, containing genes primarily expressed by naïve B cells, natural killer cells, and monocytes. The recognition of additional risk beyond HLA-DRB1 provides a new perspective on immune cell dynamics in JIA. These findings contribute to our understanding of JIA and may guide future research and therapeutic strategies.

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 < .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 > .05). And similar genotype distributions of IL12B and IL17 polymorphisms were found between the patients with nephritis and without nephritis in JSLE (P > .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.

Association between Interleukin-17F 7488A/G and 7383A/G polymorphisms and susceptibility to juvenile idiopathic arthritis

BackgroundInterleukin-17F (IL-17F), one of the cytokines, is crucial in the pathophysiology of juvenile idiopathic arthritis (JIA). Therefore, we aimed to determine the relation between IL17F 7488A/G and IL17F 7383A/G single-nucleotide polymorphisms and JIA susceptibility and to explain their impact on the disease activity.MethodsGenomic DNA of 70 patients with JIA and 70 age and sex-matched controls were extracted and typed for IL17F 7488A/G and IL17F 7383A/G single-nucleotide polymorphisms, using polymerase chain reaction with sequence-specific primers method, and compared between patients and controls.ResultsWhen compared to AA participants, children with the AG genotype of the IL17F 7488A/G and IL17F 7383A/G polymorphisms showed a substantially greater risk of JIA. Furthermore, children with the G allele were 2.8 folds more likely to have JIA than the A allele for IL17F 7488A/G polymorphism and 3.72 folds for IL17F 7383A/G polymorphism. Children with AG genotype of IL17F 7383A/G polymorphism were far more likely to have high activity JIA.ConclusionsThe G allele of both IL17F 7488A/G and IL17F7383 A/G polymorphisms is associated with increased JIA susceptibility, and JIA at High Disease Activity was more likely to develop in AG subjects of the IL17F 7383 A/G polymorphism.ImpactThe relationship between Interleukin-17F 7488A/G and 7383A/G polymorphisms and risk for JIA has not been recognized before.Impact of Interleukin-17F 7488A/G and 7383A/G genotypes on JIA disease activity.The G allele of both IL17F 7488A/G and IL17F7383 A/G polymorphisms are associated with increased JIA susceptibility.AG genotype of Interleukin-17F 7383 A/G polymorphism compared to AA patients, had a higher probability of developing JIA at a High Disease Activity (HDA) level.

Causal analysis of serum polyunsaturated fatty acids with juvenile idiopathic arthritis and ocular comorbidity.

To investigate the causal effects of plasma Polyunsaturated fatty acids (PUFAs) on the risk of juvenile idiopathic arthritis (JIA) and ocular comorbidity through Mendelian randomization (MR) analysis. Genetic variants (formerly single nucleotide polymorphisms, SNPs) that are strongly associated with PUFAs levels (P < 5×10-8) were selected as instrumental variables. Summary-level MR was performed with outcome estimates for JIA (n = 31,142) and JIA associated iridocyclitis (n = 94,197). The inverse variance-weighted (IVW) method was employed as the main approach to combine the estimation for each SNP. Two set of models with summary statistics were conducted and multiple sensitivity analyses were applied for testing of pleiotropic bias. In model 1, genetically predicted n-6 PUFAs linoleic acid (LA) and arachidonic acid (AA) were associated with lower and higher risk of JIA associated iridocyclitis using IVW (ORLA = 0.940, 95% CI: 0.895-0.988, P = 0.015; ORAA = 1.053, 95% CI: 1.007-1.101, P = 0.024). No such association was observed between each plasma PUFAs and JIA susceptibility (P > 0.05). In further MR analysis, results from model 2 also showed a consistent trend. Besides, multiple sensitivity analyses revealed that there was no obvious evidence for unknown pleiotropy (P > 0.05). Our MR study provides genetic evidence on the possible causality that plasma LA level might protect against JIA associated iridocyclitis, whereas AA was responsible for opposite effect.

Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients

BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients.MethodsWe performed genome-wide association analyses in an entire JIA case–control sample (All-JIA) and in a case–control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls.ResultsWe demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10−6), LTBP1 (P = 9,45 × 10−6), and ELMO1 (P = 1,05 × 10−5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10−6), LTBP1 (P = 9,95 × 10−6), MX1 (P = 1,65 × 10−5), and CD200R1 (P = 2,59 × 10−5).ConclusionThis study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients.Key Points• Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition.• Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe.• The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci.• The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

Genetic susceptibility to juvenile idiopathic arthritis in the Belarusian population: gene-gene interactions analysis

Background. GWASs revealed a huge amount of candidate genes for juvenile idiopathic arthritis (JIA) susceptibility. Individual SNP analysis has restrictions as an effect of each substitution may be too subtle to be detected but their interactions may significantly contribute to disease susceptibility.&#x0D; Materials and methods. 118 patients diagnosed with JIA and 202 controls were included into the study. The study was aimed to estimate interactions between SNPs of the immune and inflammatory responses genes: RUNX3 (rs11249215), RUNX1 (rs9979383), STAT4 (rs7574865), TRAF1/C5 (rs3761847), MIF (rs755622), CTLA4 (rs5742909, rs231775), PTPN2 (rs2542151) and to reveal their effects on the JIA susceptibility. SNPs were genotyped using PCR-RFLP and Real-time PCR. Multifactor dimensionality reduction analysis was performed using MDR 3.0.2 software.&#x0D; Results. RUNX3, STAT4 and PTPN2 polymorphisms were associated with systemic arthritis, RF- polyarthritis and oligoarthritis respectively. Interaction of CTLA4 (rs5742909, rs231775), TRAF1/C5 (rs3761847), RUNX1 (rs9979383), PTPN2 (rs2542151) SNPs is shown to be a risk factor for JIA (p = 0.0099).&#x0D; Conclusion. Some of the SNPs studied are associated with distinct JIA subtypes. MDR analysis identified a statistically significant high-order interaction of five polymorphisms which collectively may contribute to JIA genetic susceptibility in the Belarusian population.

Correlation between Peptidyl Arginine Deiminase Type 4 Polymorphism and Disease Activity in Polyarticular Juvenile Idiopathic Arthritis in Egyptian Patients

Background: juvenile idiopathic arthritis (JIA) is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age affecting one or more joints, lasting for at least 6 weeks. PADI4 is one member of PADI gene family. The PADI gene region is located at chromosome 1p36. It codes for enzymes responsible for the posttranslational conversion of arginine residues into citrulline. There are likely to be different genetic risk factors for JIA in different ethnic groups. Therefore, here we sought an influence of HLA-SE and PADI4 on JIA susceptibility in Japanese, because both HLA-SE and PADI4 were reported as significant genetic risk factors for RA independent of ethnicity. Recently, association of PADI4 gene polymorphisms with ACPA positivity and disease activity in polyarticular JIA. Aim of the Work: the aim of this work is to investigate PADI polymorphism rs2240340 to determine whether this polymorphism could be a marker of susceptibility to JIA in Egyptian children and adolescents and whether this single nucleotide polymorphism (SNP) is correlated with clinical parameters in JIA. Patients and Methods: the ethical approval was obtained from the hospital ethical research committee and each patient entering the study will sign an informed consent. Thirty patients included in this study with polyarticular types of juvenile idiopathic arthritis and all of them fulfilled ILAR classification criteria (2004). All were under the age of sixteen at time of diagnosis. They were recruited from Physical Medicine, Rheumatology and Rehabilitation Department at Al-Hussein and Sayed Galal University Hospitals during the period from January 2018 to June 2018. In this study we measure PADI4 polymorphism and correlate with disease activity in polyarticular JIA in Egyptian patients. Results: association of PADI4 gene polymorphisms with ACPA positivity and disease activity in polyarticular JIA and PADI4 gene polymorphism can be used as a marker of susceptibility to polyarticular JIA. Conclusion: PADI4 gene polymorphism became a marker of susceptibility to polyarticular JIA and gene polymorphism correlated with disease activity in ACPA positivity in polyarticular positive JIA.

Correlation between Peptidyl Arginine Deiminase Type 4 Polymorphism and Disease Activity in Polyarticular Juvenile Idiopathic Arthritis in Egyptian Patients

Background: juvenile idiopathic arthritis (JIA) is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age affecting one or more joints, lasting for at least 6 weeks. PADI4 is one member of PADI gene family. The PADI gene region is located at chromosome 1p36. It codes for enzymes responsible for the posttranslational conversion of arginine residues into citrulline. There are likely to be different genetic risk factors for JIA in different ethnic groups. Therefore, here we sought an influence of HLA-SE and PADI4 on JIA susceptibility in Japanese, because both HLA-SE and PADI4 were reported as significant genetic risk factors for RA independent of ethnicity. Recently, association of PADI4 gene polymorphisms with ACPA positivity and disease activity in polyarticular JIA. Aim of the Work: the aim of this work is to investigate PADI polymorphism rs2240340 to determine whether this polymorphism could be a marker of susceptibility to JIA in Egyptian children and adolescents and whether this single nucleotide polymorphism (SNP) is correlated with clinical parameters in JIA. Patients and Methods: the ethical approval was obtained from the hospital ethical research committee and each patient entering the study will sign an informed consent. Thirty patients included in this study with polyarticular types of juvenile idiopathic arthritis and all of them fulfilled ILAR classification criteria (2004). All were under the age of sixteen at time of diagnosis. They were recruited from Physical Medicine, Rheumatology and Rehabilitation Department at Al-Hussein and Sayed Galal University Hospitals during the period from January 2018 to June 2018. In this study we measure PADI4 polymorphism and correlate with disease activity in polyarticular JIA in Egyptian patients. Results: association of PADI4 gene polymorphisms with ACPA positivity and disease activity in polyarticular JIA and PADI4 gene polymorphism can be used as a marker of susceptibility to polyarticular JIA. Conclusion: PADI4 gene polymorphism became a marker of susceptibility to polyarticular JIA and gene polymorphism correlated with disease activity in ACPA positivity in polyarticular positive JIA.

CD226 and CD40 gene polymorphism in Egyptian juvenile idiopathic arthritis children: Relation to disease susceptibility and activity

Aim of the work: To study the association of CD226 rs763361 (C>T) and CD40 rs1883832 (C>T) gene polymorphism with the disease susceptibility and activity in Egyptian juvenile idiopathic arthritis (JIA) children. Patients and methods: 150 JIA children and 194 age and sex matched controls were included. CD226 (C>T) polymorphism was assessed using the tetra amplification refractory mutation system-polymerase chain reaction assay (ARMS-PCR) and restriction fragment length polymorphism (RFLP) for CD40 (C>T). The juvenile arthritis disease activity score (JADAS-27) was used to measure the patients’ disease activity. Results: The mean age of the patients was 11.2±1.7years, female: male 4:1 and the disease duration was 4.8±2.3years. 16 were systemic onset, 69 polyarticular and 65 oligoarticular and their mean JADAS-27 was 5.7±5.3. The CD226 TT genotype and T allele were significantly associated with JIA and more frequent than in control (p<0.001). The CD226 T allele was significantly higher in patients with moderate and high activity compared to mild cases (p=0.004 and p<0.001, respectively). The frequency of CD40 C allele was significantly increased in patients with severe and moderate disease activity compared to those with mild (p<0.001 and p=0.02 respectively). Conclusion: There was a genetic association between the CD226 and CD40 gene polymorphism and JIA susceptibility with an impact on disease activity in an Egyptian cohort.

Association of juvenile idiopathic arthritis with PTPN22 rs2476601 is specific to females in a Greek population.

BackgroundJuvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by persistent chronic arthritis. Disease risk is believed to be influenced by both genetic and environmental factors. It is well established that the PTPN22 single nucleotide polymorphism (SNP) rs2476601 is associated with JIA susceptibility. It was recently reported in an Australian study that this association is restricted to females and is not observed in males. A significant source of inconsistency amongst the literature on autoimmune disease susceptibility genes stems from an inability to replicate genetic findings across different racial or ethnic groups. We therefore attempted to generate further evidence of the female-specific association of rs2476601 in a homogeneous Greek population.FindingsWe genotyped rs2476601 in 128 Caucasian JIA patients (70.3 % female) and 221 healthy controls (28.1 % female) from Northern Greece. Overall, PTPN22 was associated with increased risk of JIA in this Greek sample (OR = 2.3, 95 % CI 1.1 – 5.1, p = 0.038). Sex-stratified analyses showed that, once again, the risk association was restricted to females (Female: OR = 19.9, 95 % CI 1.2 – 342, p = 0.0016; Male: OR = 1.1, 95 % CI 0.3 – 3.1, p = 0.94) supporting the prior findings.ConclusionsOur data demonstrates that this sex-specific pattern of association is broadly applicable to different populations, and provides further impetus to undertake mechanistic studies to understand the impact of sex on PTPN22 in JIA.

Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility.

BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.MethodsWe performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants.ResultsThe CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10−4). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015).ConclusionOur results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0285-3) contains supplementary material, which is available to authorized users.

Influence of Matrix metalloproteinase 1 and 3 genetic variations on susceptibility and severity of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease affecting children aged less than 16 years, characterized by chronic synovitis, cartilage damage, and bony erosions mediated by matrix metalloproteinases (MMPs), mainly MMP-1 and MMP-3. The purpose of this study was to investigate MMP-1 and MMP-3 gene polymorphisms in patients with JIA, the role of genes in susceptibility to JIA, and their associations with JIA activity and prognosis. Case-control study included 100 patients diagnosed with JIA, according to the criteria of the International League of Associations for Rheumatology (ILAR), and 100 healthy children, age and sex matched, as controls. The MMP-1 (-1607 1G/2G) and MMP-3 (-1171 5A/6A) polymorphisms were screened by polymerase chain reaction-restriction fragment length polymorphism. The serum levels of MMP-1 and MMP 3 were measured by enzyme-linked immunosorbent assay. There were significant differences between patients with JIA and control groups regarding the genotype and allele frequencies distributions of both MMP-1 1G/2G and MMP-3 5A/6A polymorphisms. The haplotype 2G-6A, which carries the abnormal alleles, showed higher frequencies in patients with JIA than in controls (OD = 2.8, P = 0.002). The prevalence of MMP-1 2G and 6A allele for MMP-3 polymorphism was found to be significantly associated with persistent oligoarticular, rheumatoid factor (RF)-positive polyarthritis, and systemic JIA groups. There were significantly increased serum levels of MMP-1 and MMP-3 associated with 2G/6A haplotype in the patient group, especially with the polyarticular RF (+ve) group than in other groups and the control group. MMP-1 and MMP-3 haplotypes could be useful genetic markers for JIA susceptibility and severity in the juvenile Egyptian population. Moreover, our data further support the use of serum MMP-3 and MMP-1 as specific markers of disease activity in JIA.

Identification of rare genetic variants in Juvenile Idiopathic Arthritis using whole exome sequencing

Juvenile Idiopathic Arthritis (JIA) is the most common form of chronic arthritis in children. JIA is characterized by onset of disease before the age of 16, with arthritis lasting >6 weeks, and with an unknown cause. Among JIA, seven sub-groups based on clinical and biological features have been individualized namely: systemic arthritis (sJIA) with autoinflammatory conditions, persistent and extended oligoarthritis (per-oJIA and ext-oJIA, respectively), rheumatoid factor-positive polyarthritis (RFpos-pJIA), enthesitis-related arthritis (ERA), psoriatic arthritis (PsA), and undifferentiated arthritis. Physiopathology of JIA is complex and JIA is considered to be a multifactorial disease due to the combination of genetic and environmental factors. Searching for genetic factors in JIA during the last decade, the introduction of genome-wide association studies (GWAS) and whole-exome sequencing have discovered several new loci associated with JIA susceptibility and have identified the disease-associated gene monogenic form of sJIA, respectively. However, despite these novel knowledge, our understanding of JIA pathogenesis still remains poorly elusive and accumulating evidence supports genetic variability as playing a key role in JIA development.

Independent confirmation of juvenile idiopathic arthritis genetic risk loci previously identified by immunochip array analysis.

BackgroundOur 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 CLARITY JIA case–control sample.FindingsGenotyping was successfully performed on a total of 404 JIA cases (mean age 6.4 years, 68% female) and 676 healthy child controls (mean age 7.1 years, 42% female) across 19 SNPs previously associated with JIA. We replicated a significant association (p < 0.05, odds ratio (OR) in a direction consistent with the previous report) for seven loci, six replicated for the first time - C5orf56-IRF1 (rs4705862), ERAP2-LNPEP (rs27290), PRR5L (rs4755450), RUNX1 (rs9979383), RUNX3 (rs4648881), and UBE2L3 (rs2266959).ConclusionsWe have carried out the first independent replication of association for six genes implicated in JIA susceptibility. Our data significantly strengthens the evidence that these loci harbor true disease associated variants. Thus, this study makes an important contribution to the growing body of international data that is revealing the genetic risk landscape of JIA.Electronic supplementary materialThe online version of this article (doi:10.1186/1546-0096-12-53) contains supplementary material, which is available to authorized users.

Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13.

In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10(-6) ) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10(-8) ], rs12411988 [OR 1.57, P = 1.16 × 10(-7) ], and rs10995450 [OR 1.31, P = 6.74 × 10(-5) ]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10(-7) for rs4688011, P = 4.33 × 10(-5) for rs6479891, P = 2.71 × 10(-5) for rs12411988, and P = 5.39 × 10(-5) for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.

The association between the functional PTPN22 1858 C/T and MIF −173 C/G polymorphisms and juvenile idiopathic arthritis: a meta-analysis

The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) 1858 C/T (rs2476601) and macrophage migration inhibitory factor (MIF) -173 C/G polymorphisms confer susceptibility to juvenile idiopathic arthritis (JIA). A meta-analysis was conducted on variant alleles versus common alleles of the PTPN22 1858 C/T and MIF -173 C/G polymorphisms across ten comparative studies, which containing 4,238 JIA patients and 6,012 normal control subjects. Ten comparative studies, consisting of nine European, and one Turkish population, were included in his meta-analysis. Meta-analysis showed an association between the T allele of the PTPN22 1858 C/T polymorphism and JIA in Europeans [odds ratio (OR) 1.311, 95% confidence interval (CI) 1.205-1.427, P<1×10(-8)]. In addition, meta-analysis revealed an association between the C allele of the MIF -173 C/G polymorphism and JIA in all subjects (OR 1.482, 95% CI 1.202-1.828, P=2.3×10(-4)). This meta-analysis confirms that the PTPN22 1858 C/T polymorphism is associated with JIA susceptibility in Europeans and shows that the MIF -173 C/G polymorphism may be associated with susceptibility to JIA.

Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap

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...

Investigation of type 1 diabetes and coeliac disease susceptibility loci for association with juvenile idiopathic arthritis

BackgroundThere is strong evidence suggesting that juvenile idiopathic arthritis (JIA) shares many susceptibility loci with other autoimmune diseases.ObjectiveTo investigate variants robustly associated with type 1 diabetes (T1D) or coeliac disease...

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis.

Recent genetic studies have led to identification of numerous loci that are associated with susceptibility to autoimmune diseases. The strategy of using information from these studies has facilitated the identification of novel juvenile idiopathic arthritis (JIA) susceptibility loci, specifically, PTPN22 and IL2RA. Several novel autoimmune susceptibility loci have recently been identified, and we hypothesise that single-nucleotide polymorphisms (SNPs) within these genes may also be JIA susceptibility loci. Five SNPs within the genes AFF3, IL2/IL21, IL7R, CTLA4 and CD226, previously associated with multiple autoimmune diseases were genotyped, in a large data set of Caucasian JIA patients and controls, and tested for association with JIA. We identified two susceptibility loci for JIA, AFF3 and the IL2/IL21 region and additional weak evidence supporting an association with the CTLA4 and IL7R genes, which warrant further investigation. All results require validation in independent JIA data sets. Further characterisation of the specific causal variants will be required before functional studies can be performed.

Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis

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...