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Interferon 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.    Methods  Expression 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.    Results  A 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.    Conclusions  Our 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.

arthritis research and therapy

Cis-regulation of IRF5 expression is unable to fully account for systemic lupus erythematosus association: analysis of multiple experiments with lymphoblastoid cell lines