Introduction We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci.

Objective. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) share some genetic factors such as HLA, PTPN22, STAT4, and 6q23. The aim of this study was to determine whether 9 other SLE genetic factors are also implicated in RA susceptibility.Methods. A characteristic single-nucleotide polymorphism (SNP) in each of 9 genetic factors, ITGAM (rs1143679), C8orf13-BLK (rs13277113), TYK2 (rs2304256), 1q25.1 (rs10798269), PXK (rs6445975), KIAA1542 (rs4963128), MECP2 (rs17435), BANK1 (rs17266594), and LY9 (rs509749), was studied in 1,635 patients with RA and 1,906 control subjects from Spain. The rs7574865 SNP in STAT4 was also included. Analyses were conducted globally and after stratification by sex and clinical features (anti-cyclic citrullinated peptide and rheumatoid factor, shared epitope, rheumatoid nodules, radiographic changes, sicca syndrome, and pneumonitis).Results. No association was observed between RA and any of the 9 newly identified SLE genetic factors. A meta-analysis using previous data was consistent with these results. In addition, there were no significant differences between individuals with and those without each of the clinical features analyzed, except the frequency of the minor allele in the C8orf13-BLK locus that was decreased in patients with sicca syndrome (14.6% versus 22.4% in controls; P ‫؍‬ 0.003).Conclusion. None of the 9 recently identified SLE risk factors showed association with RA. Therefore, common genetic factors affecting the pathogenesis of these 2 disorders seem to be limited, revealing that the genetic component contributes to the different expression of these diseases.Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) share a complex etiology encom-

IntroductionSystemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question.MethodsEuropean SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication.ResultsThere were three new associations: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR = 0.76 and 1.30, Pcorr = 0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci.ConclusionSome of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.

IntroductionWe aimed to replicate the strong associations that a recent genome wide association study (GWAS) has found between 16 single nucleotide polymorphisms (SNPs) and response to anti-tumour necrosis factor (TNF) treatment in 89 patients with rheumatoid arthritis (RA). This study is very important because, according to published simulations, associations as strong as the reported ones will mean that these SNPs could be used as predictors of response at the individual level.MethodsDisease activity score (DAS28) was evaluated in 151 anti-TNF treated patients with RA of Spanish ancestry at baseline and every 3 months thereafter. Genotypes of the 16 putative predictor SNPs were obtained by single-base extension. Association between the relative change in DAS28 and SNP genotypes was tested by linear regression. In addition, logistic regression was applied to compare genotypes in non-responders (n = 34) versus good-responders (n = 61) following the EULAR response criteria.ResultsNone of the analyses showed any significant association between the 16 SNPs and response to anti-TNF treatments at 3 or 6 months. Results were also negative when only patients treated with infliximab (66.9% of the total) were separately analyzed. These negative results were obtained in spite of a very good statistical power to replicate the reported strong associations.ConclusionsWe still do not have any sound evidence of genetic variants associated with RA response to anti-TNF treatments. In addition, the possibility we had envisaged of using the results of a recent GWAS for prediction in individual patients should be dismissed.

IntroductionInterferon regulatory factor 5 gene (IRF5) polymorphisms are strongly associated with several diseases, including systemic lupus erythematosus (SLE). The association includes risk and protective components. They could be due to combinations of functional polymorphisms and related to cis-regulation of IRF5 expression, but their mechanisms are still uncertain. We hypothesised that thorough testing of the relationships between IRF5 polymorphisms, expression data from multiple experiments and SLE-associated haplotypes might provide useful new information.MethodsExpression data from four published microarray hybridisation experiments with lymphoblastoid cell lines (57 to 181 cell lines) were retrieved. Genotypes of 109 IRF5 polymorphisms, including four known functional polymorphisms, were considered. The best linear regression models accounting for the IRF5 expression data were selected by using a forward entry procedure. SLE-associated IRF5 haplotypes were correlated with the expression data and with the best cis-regulatory models.ResultsA large fraction of variability in IRF5 expression was accounted for by linear regression models with IRF5 polymorphisms, but at a different level in each expression data set. Also, the best models from each expression data set were different, although there was overlap between them. The SNP introducing an early polyadenylation signal, rs10954213, was included in the best models for two of the expression data sets and in good models for the other two data sets. The SLE risk haplotype was associated with high IRF5 expression in the four expression data sets. However, there was also a trend towards high IRF5 expression with some protective and neutral haplotypes, and the protective haplotypes were not associated with IRF5 expression. As a consequence, correlation between the cis-regulatory best models and SLE-associated haplotypes, regarding either the risk or protective component, was poor.ConclusionsOur analysis indicates that although the SLE risk haplotype of IRF5 is associated with high expression of the gene, cis-regulation of IRF5 expression is not enough to fully account for IRF5 association with SLE susceptibility, which indicates the need to identify additional functional changes in this gene.