Human Molecular Genetics Advance Access published online on December 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm359
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Comprehensive Evaluation of the Genetic Variants of Interferon Regulatory Factor 5 Reveals a Novel 5bp Length Polymorphism as Strong Risk Factor for Systemic Lupus Erythematosus
1 Molecular Medicine, Department of Medical Sciences, Uppsala University, SE-751 Uppsala, Sweden 2 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA 3 Section of Rheumatology, Department of Medical Sciences, Uppsala University, SE-751 Uppsala, Sweden 4 Department of Biochemistry & Molecular Biology and New Jersey Medical School -University Hospital Cancer Center, UMDNJ, Newark, New Jersey, USA 5 John Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA 6 Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, SE-771 Stockholm, Sweden 7 Department of Rheumatology, Lund University Hospital, Lund, Sweden 8 Institute of Laboratory Medicine Section of MIG, Lund University, Lund, Sweden 9 Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
* Address for correspondence: Ann-Christine Syvänen, Department of Medical Sciences, Entr 70, 3rd floor, Research Department 2, Uppsala University Hospital, 75185 Uppsala, Sweden. E-mail: Ann-Christine.Syvanen{at}medsci.uu.se, Phone: +46-18-6112959 ; Fax +46-18-553601
Received September 21, 2007; Revised November 19, 2007; Accepted December 4, 2007
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 64bp 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 3 or 4 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 (PBMCs) 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.
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