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DNA Sequence Variants in Human Autoimmune Diseases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 808
Keyword [en]
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
Identifiers
URN: urn:nbn:se:uu:diva-179189ISBN: 978-91-554-8459-0 (print)OAI: oai:DiVA.org:uu-179189DiVA: diva2:549300
Public defence
2012-10-18, Enghoffsalen, University Hospital, Entrance 50, Ground Floor, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-09-27 Created: 2012-08-09 Last updated: 2013-01-23Bibliographically approved
List of papers
1. Preferential Association of Interferon Regulatory Factor 5 Gene Variants with Seronegative Rheumatoid Arthritis in 2 Swedish Case-Control Studies
Open this publication in new window or tab >>Preferential Association of Interferon Regulatory Factor 5 Gene Variants with Seronegative Rheumatoid Arthritis in 2 Swedish Case-Control Studies
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2011 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, no 10, 2130-2132 p.Article in journal (Refereed) Published
Abstract [en]

Objective.

Two interferon regulatory factor 5 (IRF5) gene variants were examined for association with rheumatoid arthritis (RA).

Methods.

A total of 2300 patients with RA and 1836 controls were recruited from 2 independent RA studies in Sweden. One insertion-deletion polymorphism (CGGGG indel) and one single-nucleotide polymorphism (rs10488631) in the IRF5 gene were genotyped and analyzed within RA subgroups stratified by rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA).

Results.

The CGGGG indel was preferentially associated with the RF-negative (OR 1.29, p = 7.9 × 10−5) and ACPA-negative (OR 1.27, p = 7.3 × 10−5) RA subgroups compared to the seropositive counterparts. rs10488631 was exclusively associated within the seronegative RA subgroups (RF-negative: OR 1.24, p = 0.016; ACPA-negative: OR 1.27, p = 4.1 × 10−3).

Conclusion.

Both the CGGGG indel and rs10488631 are relevant for RA susceptibility, especially for seronegative RA.

Keyword
rheumatoid arthritis, interferon regulatory factor 5, genetic association study, seronegative
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-162381 (URN)10.3899/jrheum.110322 (DOI)000296545400008 ()21807777 (PubMedID)
Available from: 2011-11-30 Created: 2011-11-30 Last updated: 2017-12-08Bibliographically approved
2. Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma
Open this publication in new window or tab >>Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma
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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.

Keyword
interferon regulatory factor 5, asthma, autoimmune disorder, genetic association study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-179119 (URN)10.1016/j.gene.2012.05.021 (DOI)000306775100010 ()22613848 (PubMedID)
Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
3. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations
Open this publication in new window or tab >>Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations
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2013 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 9, 994-999 p.Article in journal (Refereed) Published
Abstract [en]

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case-control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

Keyword
systemic lupus erythematosus, genetic association study, Asian, Caucasian
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-179132 (URN)10.1038/ejhg.2012.277 (DOI)000323281400016 ()
Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
4. Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility
Open this publication in new window or tab >>Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility
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2013 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 14, no 4, 217-222 p.Article in journal (Refereed) Published
Abstract [en]

The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10−5). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10−3). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.

Keyword
IKBKE, IFIH1, resequencing, association study, systemic lupus erythematosus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-179133 (URN)10.1038/gene.2013.9 (DOI)000320029300003 ()23535865 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
5. Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4
Open this publication in new window or tab >>Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4
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2013 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no 1, 96-103 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The transcription factors interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are encoded by two of the strongest susceptibility genes for systemic lupus erythematosus (SLE).

OBJECTIVE:

To investigate the target genes and functional roles of IRF5 and STAT4 in human peripheral blood mononuclear cells (PBMCs).

METHODS:

Chromatin immunoprecipitation-sequencing (ChIP-seq) was performed in PBMCs stimulated to activate IRF5 and STAT4. The expression of the target genes of IRF5 and STAT4 was investigated in a publicly available dataset generated from PBMCs from patients with SLE and healthy controls. The genomic regions bound by the transcription complexes mediated by IRF5 and STAT4 were examined for transcription factor binding motifs and SLE-associated sequence variants.

RESULTS:

More than 7000 target genes for IRF5 and STAT4 were identified in stimulated PBMCs. These genes were enriched to functional pathways in the type I interferon system, and have key roles in the inflammatory response. The expression patterns of the target genes were characteristic for patients with SLE. The transcription factors high mobility group-I/Y, specificity protein 1, and paired box 4 may function cooperatively with IRF5 and STAT4 in transcriptional regulation. Eight of the target regions for IRF5 and STAT4 contain SLE-associated sequence variants.

CONCLUSIONS:

By participating in transcription complex with other co-factors, IRF5 and STAT4 harbour the potential of regulating a large number of target genes, which may contribute to their strong association with SLE.

Keyword
interferon regulatory factor 5, signal transducer and activator of transcription 4, systemic lupus erythematosus, ChIP-seq
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-179118 (URN)10.1136/annrheumdis-2012-201364 (DOI)000312407800016 ()22730365 (PubMedID)
Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved

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