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Functional Variants in the B-Cell Gene BANK1 are Associated with Systemic Lupus Erythematosus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2008 (English)In: Nature Genetics, ISSN 1061-4036, Vol. 40, no 2, 211-216 p.Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance(1-3). In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta 2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.

Place, publisher, year, edition, pages
2008. Vol. 40, no 2, 211-216 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97762DOI: 10.1038/ng.79ISI: 000252732900020OAI: oai:DiVA.org:uu-97762DiVA: diva2:172822
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2010-01-15Bibliographically approved
In thesis
1. Genetic Risk Factors for Systemic Lupus Erythematosus: From Candidate Genes to Functional Variants
Open this publication in new window or tab >>Genetic Risk Factors for Systemic Lupus Erythematosus: From Candidate Genes to Functional Variants
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors.

Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America.

These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 395
Systemic Lupus Erythematosus, SLE, association study, complex disease, genetic
National Category
Medical Genetics
urn:nbn:se:uu:diva-9367 (URN)978-91-554-7336-5 (ISBN)
Public defence
2008-12-06, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2009-10-14Bibliographically approved

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