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Promoter Insertion/Deletion in the IRF5 Gene Is Highly Associated with Susceptibility to Systemic Lupus Erythematosus in Distinct Populations, But Exerts a Modest Effect on Gene Expression in Peripheral Blood Mononuclear Cells
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.
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2010 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 37, no 3, 574-578 p.Article in journal (Refereed) Published
Abstract [en]

Objective. We examined the genetic association of the promoter insertion/deletion (indel) in IRF5 gene with systemic lupus erythematosus (SLE) in distinct populations and assessed its role in gene expression. Methods. Four IRF5 polymorphisms were genotyped in 1488 SLE patients and 1466 controls. Gene expression was analyzed by quantitative real-time PCR using RNA from peripheral blood mononuclear cells (PBMC). Results. The promoter indel and rs2070197 had independent genetic effects, which accounted for the association of rs2004640 and rs10954213. Gene expression analysis revealed that rs10954213 exerted the greatest influence on IRF5 transcript levels. Conclusion. We corroborated the association of the promoter indel with SLE in 5 different populations and revealed that rs10954213 is the main single-nucleotide polymorphism responsible for altered IRF5 expression in PBMC.

Place, publisher, year, edition, pages
2010. Vol. 37, no 3, 574-578 p.
Keyword [en]
Gene expression, Interferon regulatory factor 5, Systemic lupus erythematosus
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-137132DOI: 10.3899/jrheum.090440ISI: 000275135700016PubMedID: 20080916OAI: oai:DiVA.org:uu-137132DiVA: diva2:377905
Available from: 2010-12-15 Created: 2010-12-15 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Functional Role of Genetic Polymorphisms Associated with Systemic Lupus Erythematosus
Open this publication in new window or tab >>Functional Role of Genetic Polymorphisms Associated with Systemic Lupus Erythematosus
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disorder characterized by a failure in the mechanism of self-tolerance and production of autoantibodies, potentially affecting any organ in the body. The genetic factors behind the disease have been extensively studied in the past years and to date a list of more than 30 loci have been associated with SLE. However, very little is known about the functional significance of the risk variants. In this thesis, we focused on the analysis of SLE-associated variants in three genes: interferon regulatory factor 5 (IRF5), CD226 and the microRNA 146a.

In paper I, we analyzed four polymorphisms in the IRF5 gene in a large set of individuals from different populations. We replicated a strong association of a promoter indel in our meta-analysis, but expression analysis indicated that it is rather another variant, SNP rs10954213 in the poly(A) signal of the gene that is in fact the major contributor to the altered gene expression in leukocytes. In manuscript II, we further characterized the regulation of IRF5 expression, showing that this gene can be up-regulated by estrogen in PBMCs and monocytes, regardless of the genotype, which could to some extent, explain the sex-bias of SLE. In paper III, we investigated the association of CD226 with SLE and the potential functional effect of the associated variants. The genetic analysis showed an association of a three-SNP-haplotype located at the 3’UTR region of the gene. The risk haplotype correlated with lower CD226 protein expression on the surface of cytotoxic and helper T cells, as well as in NK T cells. Reporter assays pointed to rs727088 in the 3’UTR as the main responsible variant for altered gene expression. In paper IV, we described the association of a variant in microRNA miR-146a, involved in the interferon pathway, with SLE in Europeans, which could in addition be correlated with decreased expression of both mature and primary miR-146a in leukocytes.

In summary, we have investigated the genetic association of three genes with SLE in a large cohort of individuals and identified variants responsible for functional alterations of these genes, providing further insight into the pathogenesis of SLE.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 736
Keyword
autoimmunity, systemic lupus erythematosus, genetic association, single nucleotide polymorphism, IRF5, CD226, miR-146a
National Category
Medical and Health Sciences Medical Genetics
Research subject
Medical Science; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-166909 (URN)978-91-554-8258-9 (ISBN)
Public defence
2012-03-02, Rudbecksalen, Dag Hammarsjölds väg 20, Rudbecklaboratoriet, Uppsala, 13:15 (English)
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Available from: 2012-02-09 Created: 2012-01-16 Last updated: 2012-02-15

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