Rheumatoid arthritis (RA), the most common autoimmune disease, is associated in families with other autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). Its genetic component has been suggested by familial aggregation (s ؍ 5), twin studies, and segregation analysis. HLA, which is the only susceptibility locus known, has been estimated to account for one-third of this component. The aim of this paper was to identify new RA loci. A genome scan was performed with 114 European Caucasian RA sib pairs from 97 nuclear families. Linkage was significant only for HLA (P < 2.5⅐10 ؊5 ) and nominal for 19 markers in 14 other regions (P < 0.05). Four of the loci implicated in IDDM potentially overlap with these regions: the putative IDDM6, IDDM9, IDDM13, and DXS998 loci. The first two of these candidate regions, defined in the RA genome scan by the markers D18S68-D18S61-D18S469 (18q22-23) and D3S1267 (3q13), respectively, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P ؍ 0.002). The analysis of all 261 families provided a linkage evidence of P ؍ 0.001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA. Candidate genes include those coding for CD80 and CD86, molecules involved in antigenspecific T cell recognition. In conclusion, this first genome scan in RA Caucasian families revealed 14 candidate regions, one of which was supported further by the study of a second set of families.
Objective.To assess the possible association between the PTPN22 gene 1858C3 T polymorphism and the predisposition and clinical expression of 2 systemic autoimmune diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).Methods. Our study population consisted of 826 RA patients, 338 SLE patients, and 1,036 healthy subjects. All subjects were of Spanish Caucasian origin. Genotyping of the PTPN22 gene 1858C3 T polymorphism was performed by real-time polymerase chain reaction technology, using the TaqMan 5-allele discrimination assay.Results. The overall distribution of genotypes in the RA patients was significantly different from that in the controls (P ؍ 0.005, by chi-square test with 2 ؋ 3 contingency tables). We observed a statistically significant difference in the distribution of the PTPN22 1858T allele between healthy subjects (7.4%), and RA patients Conclusion. These results suggest that the PTPN22 1858T allele may confer differential susceptibility to RA and SLE in the Spanish population.
Objective. The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA.Methods. Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association.Results. In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97
Objective. To investigate the osteoclastogenic potential of T cells from the peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) on autologous monocytes, and to study the cytokines implicated in this process.
Methods. T cells and monocytes were isolated
Objective. To investigate the role of the HO-1 gene as a novel functional candidate gene for rheumatoid arthritis (RA).Methods. We performed a case-control study including 736 RA patients and 846 healthy controls of Spanish Caucasian origin. Two putative functional HO-1 promoter polymorphisms, a (GT) n microsatellite and a -413 A/T single-nucleotide polymorphism (SNP), were selected as genetic markers and genotyped using polymerase chain reaction-based methods. In addition, the intracellular expression of heme oxygenase 1 (HO-1) was determined in healthy individuals with different (GT) n genotypes.Results. The distribution of HO-1 (GT) n short (S) alleles (<25 GT repeats) and long (L) alleles (>25 GT repeats) revealed a significant protective effect of S (GT) n alleles (P ؍ 0.019) (odds ratio [OR] 0.8, 95% confidence interval [95% CI] 0.7-0.9) and the SS (GT) n genotype (P ؍ 0.002) (OR 0.6, 95% CI 0.4-0.9). In contrast, the -413 HO-1 promoter SNP did not yield any statistically significant deviation between RA patients and controls, considering either allele or genotype frequencies. The haplotype analysis showed a strong protective effect of the S/A haplotype (P ؍ 7 ؋ 10 ؊7 , corrected P [P corr ] ؍ 3 ؋ 10 ؊6 ) (OR 0.4, 95% CI 0.3-0.6), whereas the L/A haplotype showed the opposite tendency (P ؍ 0.008, P corr ؍ 0.03) (OR 1.2, 95% CI 1.0-1.4). In addition, we demonstrated that monocytes from individuals carrying the SS (GT) n genotype showed a significantly higher percentage of HO-1 expression than did cells from LL homozygous individuals (P ؍ 0.0003). Conclusion. In this study, we identified the HO-1 (GT) n microsatellite as a new genetic marker involved in RA genetics in our population.
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