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Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
2007 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 4, 1234-1241 p.Article in journal (Refereed) Published
Abstract [en]

Objective. To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. Methods. Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. Results. Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5′-untranslated regions (5′-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5′-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-α. The SNP most strongly associated with SLE was SNP no. rs2070197 (P = 5.2 × 10 -11), which is a proxy of the risk haplotype, but does not appear to be functional. Conclusion. None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.

Place, publisher, year, edition, pages
2007. Vol. 56, no 4, 1234-1241 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96499DOI: 10.1002/art.22497ISI: 000245845100022PubMedID: 17393452OAI: oai:DiVA.org:uu-96499DiVA: diva2:171095
Available from: 2007-11-21 Created: 2007-11-21 Last updated: 2017-12-14Bibliographically approved
In thesis
1. The Genetics of Systemic Lupus Erythematosus: The Specificity of IRF5 to SLE.
Open this publication in new window or tab >>The Genetics of Systemic Lupus Erythematosus: The Specificity of IRF5 to SLE.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc.

The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE.

Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population.

It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 296
Keyword
Molecular genetics, Systemic lupus erythematosus, Interferon regulatory factor 5, Transmission-Disequilibrium Test, Family-based association test, Linkage Disequilibrium, Hardy-Weinberg equilibrium, Genetik
Identifiers
urn:nbn:se:uu:diva-8332 (URN)978-91-554-7038-8 (ISBN)
Public defence
2007-12-12, Rudbecksalen, Rudbeck Laboratory, 09:15
Opponent
Supervisors
Available from: 2007-11-21 Created: 2007-11-21Bibliographically approved

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