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Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Molekylär medicin)
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2008 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 45, no 6, 362-369 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be 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
2008. Vol. 45, no 6, 362-369 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-16560DOI: 10.1136/jmg.2007.055012ISI: 000256369500006PubMedID: 18285424OAI: oai:DiVA.org:uu-16560DiVA: diva2:44331
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)
Opponent
Supervisors
Available from: 2009-03-26 Created: 2009-03-07 Last updated: 2009-03-27
2. Genetic Analyses of Multiple Sclerosis and Systemic Lupus Erythematosus: From Single Markers to Genome-Wide Data
Open this publication in new window or tab >>Genetic Analyses of Multiple Sclerosis and Systemic Lupus Erythematosus: From Single Markers to Genome-Wide Data
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In autoimmune diseases an individual’s immune system becomes targeted at the body’s own healthy cells. The aim of this thesis was to identify genetic risk factors for the two autoimmune diseases multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In Study I, we found that genetic variation in the interferon regulatory factor 5 gene (IRF5), previously shown to be associated with SLE, rheumatoid arthritis and inflammatory bowel diseases, was associated also with MS. An insertion/deletion polymorphism in the first intron of IRF5 is as a good functional candidate for this association. IRF5, together with the signal transducer and activator of transcription 4 gene (STAT4), are the most important genetic risk factors for SLE, outside the HLA region. In Study II we showed using a family-based study design that genetic variation in STAT4 is associated with SLE also in the Finnish population. In Study III, we investigated a STAT4 risk allele for SLE for its association with cardiovascular disease in SLE patients. The risk allele of STAT4 proved to be strongly associated with ischemic cerebrovascular disease and anti-phospholipid antibodies in SLE patients. A possible mechanism for this association is that the risk allele leads to increased production of pro-thrombotic anti-phospholipid antibodies, which in turn increases the risk for stroke. Both IRF5 and STAT4 are involved in signalling of the type I interferon system. In Study IV, we investigated 78 additional genes in this system for their association with SLE in a Swedish cohort. The most promising results were followed up in additional patients and controls from Sweden and the US. Two novel SLE genes were identified. In Study V a large follow-up of a genome-wide association study was performed. Five new SLE loci were identified: TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10. A number of genes previously shown to be associated with other autoimmune diseases were also tested for association with SLE. This analysis identified the type I interferon system gene IFIH1 as a novel SLE risk locus. These studies confirms the central role of the type I interferon system in SLE and further suggests common genetic risk factors in autoimmunity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 528
Keyword
Systemic lupus erythematosus, Multiple Sclerosis, Association study, Type I interferon system, Single nucleotide polymorphism
National Category
Medical Genetics
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-117776 (URN)978-91-554-7736-3 (ISBN)
Public defence
2010-04-16, Enghoffsalen, University Hospital, entrance 50, ground floor, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-03-25 Created: 2010-02-22 Last updated: 2010-03-31Bibliographically approved

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