Objective. To test for associations between nonmajor histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA).Methods. Published autoimmune disease genomewide association studies were reviewed, and 519 singlenucleotide polymorphisms (SNPs) were selected for association testing. The initial cohort included 809 JIA cases and 3,535 controls of non-Hispanic, European ancestry. Of the SNPs, 257 were successfully genotyped, while 168 were imputed with quality. Based on findings in the initial cohort, replication was sought for 21 SNPs in a second cohort of 1,015 JIA cases and 1,569 controls collected in the US and Germany. For the initial cohort, tests for association were adjusted for potential confounding effects of population structure by including principal components derived from a genome-wide association study as covariates in logistic regression models. Odds ratios (ORs) and 95% confidence intervals were calculated.Results. Testing for association of previously reported autoimmune disease genetic associations in the initial cohort suggested associations with JIA in 13 distinct loci. Of these, 7 were validated in the replication cohort. Conclusion. General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms. Meta-analysis results for the replicating loci includedJuvenile idiopathic arthritis (JIA) is a childhoodonset autoimmune disorder characterized by inflammation of the joints and other tissues. The histopathology Dr.

Objective We have conducted a GWAS in a Caucasian cohort of juvenile idiopathic arthritis (JIA) patients and have previously published findings limited to autoimmune loci shared with other diseases. The goal of this study was to identify novel JIA predisposing loci using genome-wide approaches. Methods The Discovery cohort consisted of Caucasian JIA cases (814) and local controls (658) genotyped on the Affymetrix SNP 6.0 Array along with 2400 out-of-study controls. A replication study consisted of 10 SNPs genotyped in 1744 cases and 7010 controls from the US and Europe. Results Analysis within the Discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011, OR=1.37, P=1.88×10−6), and 10q21 near the gene JMJD1C [rs6479891, odds ratio (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 continued to provide evidence for association for these 4 SNPs (rs4688011, P=3.6×10−7, rs6479891, P=4.33×10−5; rs12411988, P=2.71×10−5; and rs10995450, 5.39×10−5;). Gene expression data from 68 JIA cases and 23 local controls showed cis eQTL associations for C3orf1 SNP rs4688011 (P=0.024 or P=0.034, depending on probe set) and the JMJD1C SNPs rs6479891 and rs12411988 (P=0.01 and P=0.008, respectively). A variance component liability model estimated that common SNP variation accounts for ~1/3 of JIA susceptibility. Conclusions Genetic association results and correlated gene expression findings provide evidence of association at 3q13 and 10q21 for JIA and offer novel genes as plausible candidates in disease pathology.

Objective. Levels of interleukin-6 (IL-6) have been shown to correlate with the fever and disease activity of systemic juvenile idiopathic arthritis (JIA). In a previous case-control study, a significant association between the IL-6 ؊174 nucleotide variant and systemic JIA was noted, and HeLa cell transfection assays show functional differences in levels of transcription of the IL-6 ؊174 alleles. The present study was undertaken to confirm the previous findings and to assess possible association with variations of the A n T n tract in the promoter.Methods. We studied a cohort of JIA families from 3 countries, using transmission disequilibrium testing. Genotyping of the ؊174 nucleotide variant was done by restriction fragment length polymorphism, heteroduplex analysis, or allelic discrimination. The A n T n tract at ؊392 to ؊373 was typed using DNA sequencing. Statistical analysis was performed using the programs Transmit and EHplus.Results. There was a significant excess transmission of the ؊174G allele in the systemic JIA families (P ‫؍‬ 0.041). The excess transmission was only to systemic JIA patients with age at onset >5 years (P ‫؍‬ 0.007). No significant association with the other subtypes was found. No A n T n alleles or ؊174/A n T n haplotypes were significantly associated with systemic JIA.Conclusion. This study confirms that the IL-6 -174 nucleotide variant is significantly associated with systemic JIA. The significant excess transmission to patients with age at onset >5 years but not to those with age at onset <5 years suggests that there may be genetic heterogeneity between the 2 groups.

SUMMARY:Mutations in the Xq28 gene G4.5 lead to dilated cardiomyopathy (DCM). Differential splicing of G4.5 results in a family of proteins called "tafazzins" with homology to acyltransferases. These enzymes assemble fatty acids into membrane lipids. We sequenced G4.5 in two kindreds with X-linked DCM and in two unrelated men, one with idiopathic DCM and the other with DCM of arrhythmogenic right ventricular dysplasia. We examined the ultrastructure of heart, liver, and muscle biopsy specimens in these three DCM types; we used gas chromatography to compare fatty acid composition in heart, liver, and muscle autopsy specimens of two patients of kindred 1 with that of controls. In X-linked DCM, G4.5 had a stop codon (E188X), a nonsense mutation, in kindred 1 and an amino acid substitution (G240R), a missense mutation, in kindred 2. In the two men with isolated DCM, G4.5 was not mutated. Ultrastructural mitochondrial malformations were present in the biopsy tissues of the patients with DCM. Cardiac biopsy specimens of both kindreds with X-linked DCM exhibited greatly enlarged mitochondria with large bundles of stacked, compacted, disarrayed cristae that differed from those of the two types of isolated DCM. Autopsy tissue of patients with X-linked DCM had decreased unsaturated and increased saturated fatty acid concentrations. Seven of 13 published G4.5 missense mutations, including the one presented here, occur in acyltransferase motifs. Impaired acyltransferase function could result in increased fatty acid saturation that would decrease membrane fluidity. Mitochondrial membrane proliferation may be an attempt to compensate for impaired function of acyltransferase. Cardiac ultrastructure separates X-linked DCM with G4.5 mutations from the two types of isolated DCM without G4.5 mutations. Electron microscopy of promptly fixed myocardial biopsy specimens has a role in defining the differential diagnosis of DCM. Mutational analysis of the G4.5 gene also serves this purpose. (Lab Invest 2002, 82:335-344).

To understand the mechanisms that promote recruitment and survival of T cells within the pediatric inflamed joint, we have studied the expression of CCR4 and CCR5 on synovial fluid T cells and matched peripheral blood samples from juvenile rheumatoid arthritis (JRA) patients using three-color flow cytometric analysis. Thymus- and activation-regulated chemokine and macrophage-derived chemokine, ligands for CCR4, were measured by ELISA in JRA synovial fluid, JRA plasma, adult rheumatoid arthritis synovial fluid, and normal plasma. IL-4 and IFN-γ mRNA production was assessed in CD4+/CCR4+ and CD4+/CCR4− cell subsets. We found accumulations of both CCR4+ and CCR5+ T cells in JRA synovial fluids and a correlation for increased numbers of CCR4+ T cells in samples collected early in the disease process. Thymus- and activation-regulated chemokine was detected in JRA synovial fluid and plasma samples, but not in adult rheumatoid arthritis synovial fluid or control plasma. Macrophage-derived chemokine was present in all samples. CD4+/CCR4+ synovial lymphocytes produced more IL-4 and less IFN-γ than CD4+/CCR4− cells. These findings suggest that CCR4+ T cells in the JRA joint may function early in disease in an anti-inflammatory capacity through the production of type 2 cytokines and may play a role in determining disease phenotype.