Rheumatoid Arthritis: Perez-Pampin E

Dieguez-Gonzalez R, Calaza M, Perez-Pampin E, Balsa A, Blanco FJ, Cañete JD, Caliz R, Carreño L, de la Serna AR, Fernandez-Gutierrez B, Ortiz AM, Herrero-Beaumont G, Pablos JL, Narvaez J, Navarro F, Marenco JL, Gomez-Reino JJ, Gonzalez A. · Laboratorio de Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. · Arthritis Res Ther. · Pubmed #19292917 links to  free full text

Abstract: INTRODUCTION: Genome-wide association studies of rheumatoid arthritis (RA) have identified an association of the disease with a 6q23 region devoid of genes. TNFAIP3, an RA candidate gene, flanks this region, and polymorphisms in both the TNFAIP3 gene and the intergenic region are associated with systemic lupus erythematosus. We hypothesized that there is a similar association with RA, including polymorphisms in TNFAIP3 and the intergenic region. METHODS: To test this hypothesis, we selected tag-single nucleotide polymorphisms (SNPs) in both loci. They were analyzed in 1,651 patients with RA and 1,619 control individuals of Spanish ancestry. RESULTS: Weak evidence of association was found both in the 6q23 intergenic region and in the TNFAIP3 locus. The rs582757 SNP and a common haplotype in the TNFAIP3 locus exhibited association with RA. In the intergenic region, two SNPs were associated, namely rs609438 and rs13207033. The latter was only associated in patients with anti-citrullinated peptide antibodies. Overall, statistical association was best explained by the interdependent contribution of SNPs from the two loci TNFAIP3 and the 6q23 intergenic region. CONCLUSIONS: Our data are consistent with the hypothesis that several RA genetic factors exist in the 6q23 region, including polymorphisms in the TNFAIP3 gene, like that previously described for systemic lupus erythematosus.

Dieguez-Gonzalez R, Calaza M, Perez-Pampin E, de la Serna AR, Fernandez-Gutierrez B, Castañeda S, Largo R, Joven B, Narvaez J, Navarro F, Marenco JL, Vicario JL, Blanco FJ, Fernandez-Lopez JC, Caliz R, Collado-Escobar MD, Carreño L, Lopez-Longo J, Cañete JD, Gomez-Reino JJ, Gonzalez A. · Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. · Arthritis Rheum. · Pubmed #18438842 links to  free full text

Abstract: OBJECTIVE: Previous studies have shown either a lack of effect of IRF5 polymorphisms or an association of the IRF5 gene in only a minor subset of rheumatoid arthritis (RA) patients in whom anti-citrullinated protein antibodies (ACPAs) are absent. The present study was undertaken to investigate the role of genetic variation in IRF5 in susceptibility to RA. METHODS: Nine IRF5 single-nucleotide polymorphisms (SNPs) were studied in 1,338 patients with RA and 1,342 control subjects in analyses of exploratory and replication sample collections, with stratification according to sex and by the presence or absence of ACPAs, rheumatoid factor, the shared epitope, the 620W PTPN22 allele, and erosions. A meta-analysis that included results from previous studies was also carried out. RESULTS: Our findings together with those from previous studies, in a total of 4,620 RA patients and 3,741 controls, showed a significant association of the rs2004640 IRF5 SNP in RA patients as a whole (odds ratio [OR] 0.88, 95% confidence interval [95% CI] 0.83-0.94; P = 6.5 x 10(-5) versus controls). This association was stronger in ACPA- patients, but was also present in ACPA+ patients (from 3 sample collections). Further analysis of our exploratory sample collection showed that only patients in the ACPA+ and SE- group lacked an association with IRF5 SNPs. All of the remaining RA patients (ACPA- or SE+) showed a strong association with IRF5 SNPs, which followed a complex pattern of opposing effects mediated by independent haplotypes. The susceptibility haplotype showed an OR of 1.8 (95% CI 1.4-2.3; P = 1.2 x 10(-6) versus controls), whereas the protective haplotype showed an OR of 0.76 (95% CI 0.6-0.98; P = 0.046 versus controls). CONCLUSION: IRF5 polymorphisms seem to influence RA susceptibility in a large subgroup of patients, following a pattern of association very similar to that described in patients with systemic lupus erythematosus.

Dieguez-Gonzalez R, Akar S, Calaza M, Perez-Pampin E, Costas J, Torres M, Vicario JL, Velloso ML, Navarro F, Narvaez J, Joven B, Herrero-Beaumont G, Gonzalez-Alvaro I, Fernandez-Gutierrez B, de la Serna AR, Carreño L, Lopez-Longo J, Caliz R, Collado-Escobar MD, Blanco FJ, Fernandez-Lopez C, Balsa A, Pascual-Salcedo D, Gomez-Reino JJ, Gonzalez A. · Laboratorio de Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. · Ann Rheum Dis. · Pubmed #18434448 No free full text.

Abstract: OBJECTIVE: To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)kappaB pathway, the major intracellular pathway in RA pathogenesis. METHODS: Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms (SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFkappaB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5'-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls. RESULTS: No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant. CONCLUSION: We did not find any major effect among the explored members of the NFkappaB pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.

Carmona L, Descalzo MA, Perez-Pampin E, Ruiz-Montesinos D, Erra A, Cobo T, Gómez-Reino JJ, Anonymous00127. · Research Unit, Spanish Foundation of Rheumatology, Madrid, Spain. · Ann Rheum Dis. · Pubmed #17324968 links to  free full text

Abstract: BACKGROUND: Mortality is increased in rheumatoid arthritis (RA), mainly because of cardiovascular (CV) events, cancer and infections. Recent data suggest that treatment with tumour necrosis factor (TNF) antagonists may affect this trend. OBJECTIVE: To assess whether treatment with TNF antagonists is associated with reduction in CV events, cancer and infection rates, and in mortality in patients with RA treated and not treated with TNF antagonists. METHODS: BIOBADASER is a registry for active long-term follow-up of safety of biological treatments in patients with RA. It includes 4459 patients with RA treated with TNF antagonists. EMECAR is an external RA cohort (n = 789) established to define the characteristics of the disease in Spain and to assess comorbidity. The incidence density (ischaemic heart disease) of CV events, cancer and infections was estimated and compared. The standardised mortality ratio was compared with the rate in the general population. A propensity score was used to match cohorts by the probability of being treated. RESULTS: Rates of CV and cancer events are significantly higher in EMECAR than in BIOBADASER (RR 5-7 for different CV events, and RR 2.9 for cancer), whereas the rate of serious infections is significantly higher in BIOBADASER (RR 1.6). Mortality ratio of BIOBADASER by EMECAR is 0.32 (0.20-0.53) for all causes of death, 0.58 (0.24-1.41) for CV events, 0.52 (0.21-1.29) for infection and 0.36 (0.10-1.30) for cancer-related deaths. CONCLUSION: Morbidity, other than infection, and mortality are not higher than expected in patients with RA treated with TNF antagonists.

Costas J, Perez-Pampin E, Ferreiros-Vidal I, Torres M, Phillips C, Vicario JL, Pablos JL, Carracedo A, Gomez-Reino JJ, Gonzalez A. · Research Laboratory 2, Rheumatology Unit, and National Genotyping Center, Hospital Clinco Universitario de Santiago, 15706 Santiago de Compostela, Spain. · J Rheumatol. · Pubmed #16755651 No free full text.

Abstract: OBJECTIVE: To explore the role of single nuclear polymorphisms (SNP) in 2 candidate genes, SUMO4 and MAP3K7IP2, in susceptibility to rheumatoid arthritis (RA). METHODS: Two cohorts from different Spanish towns totalling 635 patients with RA and 826 controls were studied. Six SNP were genotyped by matrix assisted laser desorption-ionization time-of-flight (MALDI-TOF) with the MassARRAY SNP genotyping system. RESULTS: We found no association with susceptibility to RA for any of the SNP including a previously described functional variant in the SUMO4 gene (163A-->G). RA susceptibility was independent of the haplotypes defined by the 6 SNP and there was also no association with clinical features of RA. Conclusion. SUMO4 and MAP3K7IP2 SNP did not significantly influence predisposition to and features of RA, in contrast to previous genetic and functional evidence that suggested their involvement.

Rodriguez-Lopez J, Perez-Pampin E, Gomez-Reino JJ, Gonzalez A. · Research Laboratory 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. · Arthritis Res Ther. · Pubmed #16356191 links to  free full text

Abstract: Many extracellular matrix (ECM) proteases seem to be important in rheumatoid arthritis (RA) and regulation of their transcription levels is a critical mechanism for controlling their activity. We have investigated, therefore, whether the best-characterized single nucleotide polymorphisms (SNPs) affecting transcription of the ECM proteases that have been related with joint pathology are associated with RA susceptibility. Nine SNPs in eight genes were selected by bibliographic search, including SNPs in the genes encoding matrix metalloproteinase (MMP)1, MMP2, MMP3, MMP7, MMP9, MMP13, plasminogen activator, tissue type (PLAT) and PAI-1. They were studied in a case-control setting that included 550 RA patients and 652 controls of Spanish ancestry from a single center. Genotyping was performed by single-base extension. Only two of the nine SNPs showed significant association with RA susceptibility. RA patients showed increased frequencies of the -7351 T allele of the gene encoding PLAT (36.4% versus 32.1% in controls, p = 0.026) and the -1306 T allele of the gene encoding MMP2 (24.5% versus 20.3% in controls, p = 0.013). These two alleles seemed to cooperate according to an additive model with respect to increased RA susceptibility (p = 0.004), and they were the low-expression alleles of the respective SNPs in a PLAT enhancer and the MMP2 promoter. These findings are in agreement with previous data suggesting that these two ECM proteases have a protective role in RA pathology. Confirmation of these associations will be needed to support these hypotheses. The remaining SNPs did not show association, either individually or collectively. Therefore, although regulatory SNPs in ECM proteases did not show any major effect on RA susceptibility, it was possible to find modest associations that, if replicated, will have interesting implications in the understanding of RA pathology.