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Replication of the TNFSF4 (OX40L) promoter region association with 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.
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2009 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, no 3, 248-253 p.Article in journal (Refereed) Published
Abstract [en]

The tumor necrosis factor ligand superfamily member 4 gene (TNFSF4) encodes the OX40 ligand (OX40L), a costimulatory molecule involved in T-cell activation. A recent study demonstrated the association of TNFSF4 haplotypes located in the upstream region with risk for or protection from systemic lupus erythematosus (SLE). To replicate this association, five single nucleotide polymorphisms (SNPs) tagging the previously associated haplotypes and passing the proper quality-control filters were tested in 1312 cases and 1801 controls from Germany, Italy, Spain and Argentina. The association of TNFSF4 with SLE was replicated in all the sets except Spain. There was a unique risk haplotype tagged by the minor alleles of the SNPs rs1234317 (pooled odds ratio (OR)=1.39, P=0.0009) and rs12039904 (pooled OR=1.38, P=0.0012). We did not observe association to a single protective marker (rs844644) or haplotype as the first study reported; instead, we observed different protective haplotypes, all carrying the major alleles of both SNPs rs1234317 and rs12039904. Association analysis conditioning on the haplotypic background confirmed that these two SNPs explain the entire haplotype effect. This first replication study confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE.

Place, publisher, year, edition, pages
2009. Vol. 10, no 3, 248-253 p.
Keyword [en]
systemic lupus erythematosus, TNFSF4, OX40L, genetic association study
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-102306DOI: 10.1038/gene.2008.95ISI: 000265961300006PubMedID: 19092840OAI: oai:DiVA.org:uu-102306DiVA: diva2:214621
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2013-08-30Bibliographically approved
In thesis
1. Dissecting the Genetic Basis of Systemic Lupus Erythematosus: The Pursuit of Functional Variants
Open this publication in new window or tab >>Dissecting the Genetic Basis of Systemic Lupus Erythematosus: The Pursuit of Functional Variants
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease that primarily affects women during the childbearing years. SLE is characterized by the production of autoantibodies against nucleic acids and their interacting proteins. The exact molecular mechanisms leading to the breakdown of self-tolerance remain to a large extent unknown, but it is well established that they are influenced by both non-genetic (i.e. environmental and hormonal) and genetic factors. SLE is a complex, polygenic disease. Several susceptibility variants have been identified in SLE. However, the functional role in disease pathogenesis for the majority of them remains largely unknown.

This thesis includes case-control association studies where the role of the genes TNFSF4 (Paper I), STAT4 (Paper II), CD226 (Paper III), and BLK (Papers IV and V) in the susceptibility of developing SLE was investigated. The primary focus was on the identification of the functional variants underlying the association. For each of these genes, fine mapping was performed using single nucleotide polymorphisms (SNPs), the linkage disequilibrium (LD) was characterized, and the association was narrowed down to specific haplotypes by means of several different statistical genetic strategies. Candidate variants were prioritized for further functional analysis on the basis of their potential effect on the gene function, their association, and/or biological plausibility. In Paper I, the association of TNFSF4 with SLE was validated and attributed to a risk haplotype tagged by SNPs rs1234317-T and rs12039904-T. Paper II provides evidence supporting the presence of at least two independent genetic effects within the STAT4 gene represented by rs3821236-A and rs7574865-A, which correlated with increased levels of gene expression. In Paper III, a functional allele in CD226 (rs727088-C) was identified, which was responsible for decreased levels in both mRNA and protein expression. In Paper IV, two independent genetic effects in the BLK gene were demonstrated. The first one comprised multiple regulatory variants in high LD that were enriched for NFκB and IRF4 binding sites and correlated with low BLK mRNA levels. The second was a low-frequency missense substitution (Ala71Thr) that decreased the BLK protein half-life. In Paper V, a genetic epistatic interaction between BANK1 rs10516487 (GG) and BLK rs2736340 (TT+TC) was demonstrated. Additional molecular analyses established that these molecules interact physically.  

These studies have contributed to the dissection of the genetic architecture of SLE. They highlight the allelic heterogeneity of the disease and provide functional links to the associated variants, which has significantly aided in the understanding of SLE disease pathogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 88 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 876
Systemic Lupus Erythematosus, SLE, Genetic Mapping, Association Studies, Functional Variants, TNFSF4, STAT4, IRF5, CD226, BLK, BANK1, Systemisk Lupus Erythematosus, SLE, Genetik, Genetisk Association, Funktionella Varianter, TNFSF4, STAT4, IRF5, CD226, BLK, BANK1, Lupus Eritematoso Sistémico, LES, Estudios de Asociación Genética, Variantes Funcionales, TNFSF4, STAT4, IRF5, CD226, BLK, BANK1
National Category
Medical Genetics Genetics
Research subject
Medical Genetics; Medical Science
urn:nbn:se:uu:diva-196428 (URN)978-91-554-8620-4 (ISBN)
Public defence
2013-04-26, Rudbecksalen, The Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2013-04-05 Created: 2013-03-08 Last updated: 2013-08-30Bibliographically approved

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Alarcón-Riquelme, Marta E.
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