TY - JOUR
T1 - Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus
AU - Kozyrev, Sergey V.
AU - Abelson, Anna Karin
AU - Wojcik, Jerome
AU - Zaghlool, Ammar
AU - Linga Reddy, M. V.Prasad
AU - Sanchez, Elena
AU - Gunnarsson, Iva
AU - Svenungsson, Elisabet
AU - Sturfelt, Gunnar
AU - Jönsen, Andreas
AU - Truedsson, Lennart
AU - Pons-Estel, Bernardo A.
AU - Witte, Torsten
AU - D'Alfonso, Sandra
AU - Barrizzone, Nadia
AU - Danieli, Maria Giovanna
AU - Gutierrez, Carmen
AU - Suarez, Ana
AU - Junker, Peter
AU - Laustrup, Helle
AU - González-Escribano, Maria Francisca
AU - Martin, Javier
AU - Abderrahim, Hadi
AU - Alarcón-Riquelme, Marta E.
N1 - Funding Information:
The authors would like to express their gratitude to S. Lewén for help with purification of PBMCs and total RNA, H. Yin for help with the preparation of DNA samples and to the members of the Uppsala Genome Center for help with sequencing. We thank T. Bergström and L. Cavelier (Uppsala University) for providing RNA from chimpanzee spleen. We also thank A.I. Scollo, A.M. Perichon and M.C.R. Tenaglia (CEDIM, Diagnóstico Molecular y Forense SRL, Rosario, Argentina) for their help in DNA preparation of the Argentine samples and A. Voss for clinical help with the Danish samples. The authors would like to thank particularly the Lupus Patient Association of Asturias for their help in the collection of samples as well as all the patients for their contribution. The authors would also like to thank J.Osorio y Fortea (Pasteur Institut, Paris) for his contribution in the analyses that led to the identification of R61H early in this project. This work has been supported in part by grants from the European CVDIMMUNE project from the European Commission LSHM-CT-2006-037227, Swedish Research Council for Medicine (12703), the Swedish Association against Rheumatism, the Magnus Bergwalls Foundation, the Gustaf V: 80th-year Jubilee Foundation, the Torsten and Ragnar Söderbergs Foundation and the Marcus Borsgtröms Foundation to M.E.A.-R. and by the Gurli and Edward Brunnbergs Foundation for rheumatologic research to S.V.K. M.E.A.-R. is supported by an award from the Knut and Alice Wallenberg Foundation through the Royal Swedish Academy of Sciences. This work was also partially supported by FISM, Regione Piemonte (CIPE), the Bundesministerium für Bildung und Forschung (BMBF) Kompetenznetz Rheuma C2.12, Germany and the Danish Rheumatism Association.
PY - 2008/2
Y1 - 2008/2
N2 - 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 × 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 (Δ2), 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.
AB - 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 × 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 (Δ2), 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.
UR - https://www.scopus.com/pages/publications/38649138296
U2 - 10.1038/ng.79
DO - 10.1038/ng.79
M3 - Article
SN - 1061-4036
VL - 40
SP - 211
EP - 216
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -