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Functional Role of Genetic Polymorphisms Associated with Systemic Lupus Erythematosus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. (Prof. Ulf Gyllensten)
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. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 736
Keyword [en]
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: urn:nbn:se:uu:diva-166909ISBN: 978-91-554-8258-9 (print)OAI: oai:DiVA.org:uu-166909DiVA: diva2:479546
Public defence
2012-03-02, Rudbecksalen, Dag Hammarsjölds väg 20, Rudbecklaboratoriet, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2012-02-09 Created: 2012-01-16 Last updated: 2018-01-12
List of papers
1. 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
Open this publication in new window or tab >>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
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2010 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 37, no 3, p. 574-578Article 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.

Keyword
Gene expression, Interferon regulatory factor 5, Systemic lupus erythematosus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-137132 (URN)10.3899/jrheum.090440 (DOI)000275135700016 ()20080916 (PubMedID)
Available from: 2010-12-15 Created: 2010-12-15 Last updated: 2017-12-11Bibliographically approved
2. Estrogen-dependent upregulation of IRF5 in human immune cells
Open this publication in new window or tab >>Estrogen-dependent upregulation of IRF5 in human immune cells
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: To contribute to the knowledge of the mechanisms behind the strong sex-biased prevalence of SLE, we investigated the role of estrogen on the expression of one of the strongest associated gene with SLE, the interferon regulatory factor 5 (IRF5), in human immune cells.

Material and methods:  IRF5, as well as IRF3, IRF4, IRF7 and IRF9 expression was measured in PBMCs, LCLs, monocytes and macrophages from both male and female origin. Cells were treated with different concentrations of estrogen and gene expression was measured by quantitative RT-PCR.

Results: We found that the initial levels of IRF5 in PBMC were almost 2-fold higher in women than men, although not reaching statistical significance. After 12 h in culture the IRF5 levels became roughly equal in both sexes, and further stimulation with estrogen lead to up-regulation of IRF5 expression in both PBMCs and monocytes in both women and men. No difference was seen for IRF3, IRF4, IRF7 and IRF9 expression, and no gene was up-regulated in LCLs, upon estrogen treatment, regardless of the gender.

Conclusions: We showed that in human PBMCs and monocytes from healthy individuals IRF5 expression can be regulated by exogenous estrogen. This feature might be specific to IRF5 since four other IRF genes tested did not show any up-regulation in these cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-166901 (URN)
Available from: 2012-01-16 Created: 2012-01-16 Last updated: 2012-02-10
3. A 3 '-Untranslated Region Variant Is Associated With Impaired Expression of CD226 in T and Natural Killer T Cells and Is Associated With Susceptibility to Systemic Lupus Erythematosus
Open this publication in new window or tab >>A 3 '-Untranslated Region Variant Is Associated With Impaired Expression of CD226 in T and Natural Killer T Cells and Is Associated With Susceptibility to Systemic Lupus Erythematosus
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2010 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 11, p. 3404-3414Article in journal (Refereed) Published
Abstract [en]

Objective. Costimulatory receptor CD226 plays an important role in T cell activation, differentiation, and cytotoxicity. This study was undertaken to investigate the genetic association of CD226 with susceptibility to systemic lupus erythematosus (SLE) and to assess the functional implications of this association. Methods. Twelve tag single-nucleotide polymorphisms (SNPs) in CD226 were typed in 1,163 SLE patients and 1,482 healthy control subjects from Europe or of European ancestry. Analyses of association were performed by single-marker Cochran-Mantel-Haenszel meta-analysis, followed by haplotype analysis. Gene expression was analyzed by quantitative real-time polymerase chain reaction analyses of RNA from peripheral blood mononuclear cells, and by fluorescence-activated cell sorter analysis. To study the functional impact of the associated variants, luciferase reporter constructs containing different portions of the 3'-untranslated region (3'-UTR) of the gene were prepared and used in transfection experiments. Results. A 3-variant haplotype, rs763361; rs34794968; rs727088 (ATC), in the last exon of CD226 was associated with SLE (P = 1.3 x 10(-4), odds ratio 1.24, 95% confidence interval 1.11-1.38). This risk haplotype correlated with low CD226 transcript expression and low CD226 protein levels on the surface of CD4+ and CD8+ T cells and natural killer T (NKT) cells. NK cells expressed high levels of CD226, but this expression was independent of the haplotype. Reporter assays with deletion constructs indicated that only the presence of rs727088 could account for the differences in the levels of luciferase transcripts. Conclusion. This study identified an association of CD226 with SLE in individuals of European ancestry. These data support the importance of the 3'-UTR SNP rs727088 in the regulation of CD226 transcription both in T cells and in NKT cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-134128 (URN)10.1002/art.27677 (DOI)000283776400032 ()
Available from: 2010-11-22 Created: 2010-11-22 Last updated: 2017-12-12Bibliographically approved
4. Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene
Open this publication in new window or tab >>Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene
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2012 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 13, no 3, p. 268-274Article in journal (Refereed) Published
Abstract [en]

A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.

National Category
Medical and Health Sciences
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-166899 (URN)10.1038/gene.2011.84 (DOI)000303059900009 ()
Available from: 2012-01-16 Created: 2012-01-16 Last updated: 2017-12-08Bibliographically approved

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