TY - JOUR
T1 - 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
AU - Sigurdsson, Snaevar
AU - Göring, Harald H.H.
AU - Kristjansdottir, Gudlaug
AU - Milani, Lili
AU - Nordmark, Gunnel
AU - Sandling, Johanna K.
AU - Eloranta, Maija Leena
AU - Feng, Di
AU - Sangster-Guity, Niquiche
AU - Gunnarsson, Iva
AU - Svenungsson, Elisabet
AU - Sturfelt, Gunnar
AU - Jönsen, Andreas
AU - Truedsson, Lennart
AU - Barnes, Betsy J.
AU - Alm, Gunnar
AU - Rönnblom, Lars
AU - Syvänen, Ann Christine
N1 - Funding Information:
The study was supported by a Target Identification in Lupus (TIL) grant from the Alliance for Lupus Research, USA, by grants from the Swedish Research Council for Medicine, Agnes and Mac Rudberg’s Foundation and from the Knut and Alice Wallenberg Foundation, the Swedish Rheumatism Association, Centre of Gender related Medicine at Karolinska Institutet, the Swedish Heart-Lung Foundation, the Åke Wiberg foundation, the King Gustaf V 80-year Foundation and Ulla and Roland Gustafsson Foundation. Development of SOLAR is supported by a grant from the US National Institutes of Mental Health (MH059490). The study was is part supported by a grant to B.J.B from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03AR054070). Funding to pay Open Access publication charges for this article was provided by the Swedish Research Council for Medicine.
PY - 2008/3/15
Y1 - 2008/3/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddm359
DO - 10.1093/hmg/ddm359
M3 - Article
C2 - 18063667
AN - SCOPUS:40649121122
VL - 17
SP - 872
EP - 881
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 6
ER -