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Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

Kozyrev, Sergey V; Abelson, Anna-Karin; Wojcik, Jerome; Zaghlool, Ammar; Reddy, M V Prasad Linga; Sanchez, Elena; Gunnarsson, Iva; Svenungsson, Elisabet; Sturfelt, Gunnar LU and Jönsen, Andreas LU , et al. (2008) In Nature Genetics 40(2). p.211-216
Abstract
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,... (More)
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. (Less)
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@article{c3fc9ef9-bdf9-487b-b35d-f990af451a02,
  abstract     = {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.},
  author       = {Kozyrev, Sergey V and Abelson, Anna-Karin and Wojcik, Jerome and Zaghlool, Ammar and Reddy, M V Prasad Linga and Sanchez, Elena and Gunnarsson, Iva and Svenungsson, Elisabet and Sturfelt, Gunnar and Jönsen, Andreas and Truedsson, Lennart and Pons-Estel, Bernardo A and Witte, Torsten and D'Alfonso, Sandra and Barrizzone, Nadia and Danieli, Maria Giovanna and Gutierrez, Carmen and Suarez, Ana and Junker, Peter and Laustrup, Helle and Gonzalez-Escribano, Maria Francisca and Martin, Javier and Abderrahim, Hadi and Alarcon-Riquelme, Marta E},
  issn         = {1546-1718},
  language     = {eng},
  number       = {2},
  pages        = {211--216},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus},
  url          = {http://dx.doi.org/10.1038/ng.79},
  volume       = {40},
  year         = {2008},
}