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Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma
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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2012 (English)In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 504, no 2, 220-225 p.Article in journal (Refereed) Published
Abstract [en]

Asthma is a heterogeneous disorder hallmarked by chronic inflammation in the respiratory system. Exacerbations of asthma are correlated with respiratory infections. Considering the implication of interferon regulatory factor 5 (IRF5) in innate and adaptive immunity, we investigated the preferential transmission patterns of ten IRF5 gene polymorphisms in two asthmatic family cohorts. A common IRF5 haplotype was found to be associated with asthma and the severity of asthmatic symptoms. Stratified analysis of subgroups of asthmatic individuals revealed that the associations were more pronounced in nonatopic asthmatic individuals. In addition, the risk alleles of IRF5 polymorphisms for asthma were almost completely opposite to those for autoimmune disorders. Our study provides the first evidence of association between IRF5 and asthma, and sheds light on the related but potentially distinct roles of IRF5 alleles in the pathogenesis of asthma and autoimmune disorders.

Place, publisher, year, edition, pages
2012. Vol. 504, no 2, 220-225 p.
Keyword [en]
interferon regulatory factor 5, asthma, autoimmune disorder, genetic association study
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-179119DOI: 10.1016/j.gene.2012.05.021ISI: 000306775100010PubMedID: 22613848OAI: oai:DiVA.org:uu-179119DiVA: diva2:543450
Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2013-01-23Bibliographically approved
In thesis
1. DNA Sequence Variants in Human Autoimmune Diseases
Open this publication in new window or tab >>DNA Sequence Variants in Human Autoimmune Diseases
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human autoimmune diseases are hallmarked by inappropriate loss-of-tolerance and self-attacking response of the immune system. Studies included in this thesis are focusing on the implication and functional impact of genetic factors in three autoimmune diseases rheumatoid arthritis (RA), asthma, and systemic lupus erythematosus (SLE).

Using genetic association studies, we found in study I and II that sequence variants of the interferon regulatory factor 5 (IRF5) gene were associated with RA and asthma, and the associations were more pronounced in certain disease subtypes. Distinct association patterns or risk alleles of the IRF5 gene variants were revealed in different diseases, indicating that IRF5 contributes to disease manifestations in a dose-dependent manner. In study III, we found that seven out of eight genetic risk loci for SLE, which were originally identified in East Asian populations, also conferred disease risk with the same risk alleles and comparable magnitudes of effect sizes in Caucasians. Remarkable differences in risk allele frequencies were observed for all associated loci across ethnicities, which seems to be the major source of genetic heterogeneity for SLE. In study IV we explored an exhaustive spectrum of sequence variants in the genes inhibitor of kappa light polypeptide gene enhancer in B-cells kinase epsilon (IKBKE) and interferon induced with helicase C domain 1 (IFIH1) by gene resequencing, and identified nine variants in IKBKE and three variants in IFIH1 as genetic risk factors for SLE. One of the associated variants may influence splicing of IKBKE mRNA. In study V we provided genome-wide transcriptional regulatory profiles for IRF5 and signal transducer and activator of transcription 4 (STAT4) using chromatin immunoprecipitation-sequencing (ChIP-seq). The target genes of IRF5 and STAT4 were found to play active roles in pathways related with inflammatory response, and their expression patterns were characteristic for SLE patients. We also identified potential cooperative transcription factors for IRF5 and STAT4, and disease-associated sequence variants which may affect the regulatory function of IRF5 and STAT4.

In conclusion, this thesis illuminates the contribution of several genetic risk factors to susceptibility of human autoimmune diseases, which facilitates our understanding of the genetic basis of their pathogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 808
Association study, Gene resequencing, ChIP-seq, Type I interferon system, Systemic lupus erythematosus, Rheumatoid arthritis, Asthma
National Category
Medical and Health Sciences
Research subject
Medical Genetics; Molecular Genetics
urn:nbn:se:uu:diva-179189 (URN)978-91-554-8459-0 (ISBN)
Public defence
2012-10-18, Enghoffsalen, University Hospital, Entrance 50, Ground Floor, Uppsala, 09:15 (English)
Available from: 2012-09-27 Created: 2012-08-09 Last updated: 2013-01-23Bibliographically approved

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