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Comprehensive evalu...
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
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- Sigurdsson, Snaevar (author)
- Uppsala universitet,Molekylär medicin
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Göring, Harald H. H. (author)
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- Kristjansdottir, Gudlaug (author)
- Uppsala universitet,Molekylär medicin
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- Milani, Lili (author)
- Uppsala universitet,Molekylär medicin
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- Nordmark, Gunnel (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Sandling, Johanna K. (author)
- Uppsala universitet,Molekylär medicin
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- Eloranta, Maija-Leena (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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Feng, Di (author)
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Sangster-Guity, Niquiche (author)
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- Gunnarsson, Iva (author)
- Karolinska Institutet
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- Svenungsson, Elisabet (author)
- Karolinska Institutet
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- Sturfelt, Gunnar (author)
- Lund University,Lunds universitet,Reumatologi och molekylär skelettbiologi,Sektion III,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Rheumatology,Section III,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Jönsen, Andreas (author)
- Lund University,Lunds universitet,Reumatologi och molekylär skelettbiologi,Sektion III,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Rheumatology,Section III,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Truedsson, Lennart (author)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine
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Barnes, Betsy J. (author)
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Alm, Gunnar (author)
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- Rönnblom, Lars (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Syvänen, Ann-Christine (author)
- Uppsala universitet,Molekylär medicin
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(creator_code:org_t)
- 2007-12-06
- 2008
- English.
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:6, s. 872-881
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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Sigurdsson, Snae ...
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Göring, Harald H ...
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Kristjansdottir, ...
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Milani, Lili
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Nordmark, Gunnel
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Sandling, Johann ...
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Eloranta, Maija- ...
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Feng, Di
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Sangster-Guity, ...
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Gunnarsson, Iva
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Svenungsson, Eli ...
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Sturfelt, Gunnar
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Jönsen, Andreas
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Truedsson, Lenna ...
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Barnes, Betsy J.
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Alm, Gunnar
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Rönnblom, Lars
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Syvänen, Ann-Chr ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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Human Molecular ...
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Uppsala University
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Karolinska Institutet
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Lund University