Cis-regulation of IRF5expression is unable to fully account for systemic lupus erythematosus association: analysis of multiple experiments with lymphoblastoid cell lines
| Autor: | Juan J. Gomez-Reino, Elisa Alonso-Perez, Tony Kwan, Manuel Calaza, Antonio Gonzalez, Jacek Majewski, Marian Suarez-Gestal |
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| Přispěvatelé: | Universidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina |
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Disease susceptibility lymphoblastoid cell lines Immunology cis-regulation Gene Expression Biology Risk Assessment Cell Line Systemic lupus erythematosus Rheumatology systemic lupus erythematosus immune system diseases Risk Factors Internal medicine IRF5 Gene expression medicine Immunology and Allergy Humans Lupus Erythematosus Systemic Genetic Predisposition to Disease Lymphocytes skin and connective tissue diseases Gene Genetic association Genetics Polymorphism Genetic Haplotype Genetic Complementation Test Cis-regulation disease susceptibility linear regression models Linear regression models Haplotypes Cell culture Interferon Regulatory Factors Linear Models Interferon regulatory factors Research Article |
| Zdroj: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname Arthritis Research & Therapy RUNA. Repositorio da Consellería de Sanidade e Sergas Servizo Galego de Saúde (SERGAS) |
| Popis: | Introduction 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. This project was supported by grants PI06/0620 and PI080744 from the Instituto de Salud Carlos III (Spain) with funds from European Regional Development Fund (European Union) SI |
| Databáze: | OpenAIRE |
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