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Purpose: Variants in the gene encoding Programmed Cell Death-1 (PDCD1) have been associated with susceptibility to Systemic Lupus Erythematosus and other autoimmune diseases. Given that clinically distinct autoimmune phenotypes share common genetic susceptibility factors, variants in PDCD-1 were tested for a possible association with Juvenile Idiopathic Arthritis (JIA)., Methods: Four Single Nucleotide Polymorphisms (SNPS) in the PDCD1 gene were genotyped and analyzed: rs7421861, rs11568821, rs10204525, and rs7568402 in 834 cases and 855 controls of Northern European ancestry. Each variant was examined for possible associations with JIA and then analyzed for association with JIA categories., Results: PDCD1 variants showed no association with JIA in the cohort overall (rs7421861 p=0.63, rs11568821 p=0.13, rs10204525 p=0.31, and rs7568402 p=0.45). Stratification by JIA categories indicated a significant association between systemic JIA and PDCD1 rs7568402 (OR=0.53, p=0.0027), which remained significant after 10,000 permutations, but was not replicated in an independent multi-ethnic systemic JIA cohort. A nominal association between enthesitis-related arthritis and rs115668821 was also observed (OR=0.22, p=0.012)., Conclusion: Unlike other multiple autoimmune disease associated genetic variants, there was no association between PDCD1 variants and JIA or JIA categories., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

Objective: Children with childhood-onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. To test the hypothesis that adult-onset RA-associated variants are also associated with childhood-onset RA, we investigated RA-associated variants at 5 loci in a cohort of patients with childhood-onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood-onset RA using a weighted genetic risk score (wGRS)., Methods: A total of 155 children with childhood-onset RA and 684 healthy controls were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with childhood-onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood-onset RA., Results: Childhood-onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44-0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11-2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 1.06-1.87]) variants. The wGRS was significantly different between cases and controls (P < 2 × 10(-16) ). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood-onset RA, especially among males., Conclusion: The magnitude and direction of the association between TNFAIP3, STAT4, and PTPN22 variants and childhood-onset RA are similar to those observed in RA, suggesting that adult-onset RA and childhood-onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA-associated variants with susceptibility to childhood-onset RA., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE., Methods: High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S(2) , S(3P) , or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al., Results: We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10(-7) ). We also observed associations between individual SE alleles (HLA-DRB1*0101, *0401, *0404, *0405, *0408, and *1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S(2) /S(3P) (OR 22.3, 95% CI 9.9-50.5, P < 0.0001)., Conclusion: We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S(2) and S(3P) risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA., (Copyright © 2012 by the American College of Rheumatology.)

Objective: Reactive oxygen species (ROS) contribute to oxidative lung injury. The glutathione-S-transferases (GST) family and microsomal epoxide hydrolase (mEPHx) enzymes detoxify ROS, and genetic polymorphisms alter this detoxification. We hypothesized that polymorphisms encoding for less efficient enzymes were associated with bronchopulmonary dysphasia (BPD)., Study Design: We determined allelic distribution of these polymorphisms in a pilot study of 35 BPD cases and 98 controls. chi2 and regression analysis were performed., Results: GST P1 val105ile distribution differed between the groups, with the more efficient val/val allele predominantly in controls (p< or =0.05). When controlling for race and sex, BPD cases were less likely to be homozygotes for the val/val isoform (OR 0.21, CI: 0.045-0.95, p=0.04) and more likely to possess the less efficient ile isoform (OR 4.5, CI: 1.0-20.7, p=0.05)., Conclusions: This pilot study suggests that BPD is associated with the presence of the GST-P1 105ile allele. Future prospective studies are warranted.