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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
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2008 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 6, 872-881 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 17, no 6, 872-881 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-16567DOI: 10.1093/hmg/ddm359ISI: 000253832700011PubMedID: 18063667OAI: oai:DiVA.org:uu-16567DiVA: diva2:44338
Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Genetic Variation and Expression of the IRF5 Gene in Autoimmune Diseases
Open this publication in new window or tab >>Genetic Variation and Expression of the IRF5 Gene in Autoimmune Diseases
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune response. The IRF5 gene has received considerable attention since it was shown to be associated with two autoimmune diseases; systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim of this thesis was to examine if IRF5 is associated with other autoimmune diseases and to investigate the role of the genetic variation of IRF5. In the first study a set of common polymorphisms in IRF5 were analyzed for their association with two subgroup of inflammatory bowel disease (IBD); Crohn´s diseases (CD) and ulcerative colitis (UC). A strong signal of association of IRF5 with IBD was found. The most strongly associated polymorphism is a 5 base pair (bp) insertion-deletion (indel) in the promoter region of the IRF5 gene. The association was detected within both UC and CD, and appeared to be stronger in UC. In the second study we investigated the association of IRF5 with multiple sclerosis (MS). A similar set of polymorphisms as in the IBD study were genotyped in a cohort of MS patients and controls. The same polymorphisms that were associated with IBD were also found to be associated with MS. In the third study, we performed a comprehensive investigation of the IRF5 gene to detect most of the polymorphisms in the gene, and to determine to what extent they account for the association signals obtained from the gene. IRF5 was sequenced and 34 new polymorphisms were identified. Twenty seven of these, and 20 previously known SNPs in IRF5 were genotyped in an SLE case-control cohort. We found that only two polymorphisms, the 5bp indel and a SNP downstream of IRF5, account for the association signal from all the remaining markers in the IRF5 gene, and that these two polymorphisms are independently associated with SLE. Interestingly, in our studies on IBD and MS, we only observed the signal from the 5bp indel polymorphism as a risk factor for IBDs. In the fourth study the two independent risk alleles in IRF5, were tested for their association with primary Sjögren´s syndrome (pSS). In this study we also included one SNP in the STAT4 gene, since STAT4 had recently been shown to be associated with SLE. Both risk factors in IRF5 and STAT4 were found to be associated with pSS.

The regulation of expression of IRF5 was also investigated in the first three studies. We observed allele-specific differences in protein binding as well as increased binding of the transcription factor SP1 to the 5bp risk allele. We also detected increased expression of the IRF5 mRNA from a promoter containing the risk allele.

Taken together, the results of our studies suggest a general function for IRF5 as a regulator of the autoimmune response, where the 5bp indel is associated with IBD, MS, SLE and pSS. The additionally polymorphisms, which account for the remaining association signal obtained with SLE and pSS, may contribute to the disease manifestations that are specific for rheumatic diseases. Our studies add to the evidence that there are genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 434
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-99098 (URN)978-91-554-7450-8 (ISBN)
Public defence
2009-04-16, Enghoffsalen, Akademiska sjukhuset, ingång 50, bv, 09:00 (English)
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Available from: 2009-03-26 Created: 2009-03-07 Last updated: 2009-03-27

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