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- Title
Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus.
- Authors
Kozyrev, Sergey V; Abelson, Anna-Karin; Wojcik, Jerome; Zaghlool, Ammar; Linga Reddy, M V Prasad; Sanchez, Elena; Gunnarsson, Iva; Svenungsson, Elisabet; Sturfelt, Gunnar; Jönsen, Andreas; Truedsson, Lennart; Pons-Estel, Bernardo A; Witte, Torsten; D'Alfonso, Sandra; Barizzone, Nadia; Danieli, Maria Giovanna; Gutierrez, Carmen; Suarez, Ana; Junker, Peter; Laustrup, Helle; González-Escribano, Maria Francisca; Martin, Javier; Abderrahim, Hadi; Alarcón-Riquelme, Marta E
- Abstract
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance. 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 (Delta2), 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.
- Publication
Nature genetics, 2008, Vol 40, Issue 2, p211
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.79