Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus

• Published in: Human molecular genetics Vol. 17; no. 6; pp. 872 - 881
• Main Authors: Sigurdsson, Snaevar, Göring, Harald H.H., Kristjansdottir, Gudlaug, Milani, Lili, Nordmark, Gunnel, Sandling, Johanna K., Eloranta, Maija-Leena, Feng, Di, Sangster-Guity, Niquiche, Gunnarsson, Iva, Svenungsson, Elisabet, Sturfelt, Gunnar, Jönsen, Andreas, Truedsson, Lennart, Barnes, Betsy J., Alm, Gunnar, Rönnblom, Lars, Syvänen, Ann-Christine
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.03.2008; Oxford Publishing Limited (England)
• Subjects: Base Pairing; Basic Medicine; Biological and medical sciences; Blotting, Western; Case-Control Studies; Electrophoretic Mobility Shift Assay; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Humans; Interferon Regulatory Factors - genetics; Lupus Erythematosus, Systemic - genetics; Medical and Health Sciences; Medical Genetics; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Molecular and cellular biology; Polymorphism, Single Nucleotide; Risk Factors; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Immunopathology; Connective tissue disease; Skin disease; Systemic lupus erythematosus; IRF3 factor; Genetic variant; Systemic disease; Risk factor; Autoimmune disease; Genetics; Interferon regulatory factor; Polymorphism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddm359

We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3′ of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.