title: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus.
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.
authors.affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozyrev
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Abelson
authors.forename: Jerome
authors.initials: J
authors.lastname: Wojcik
authors.forename: Ammar
authors.initials: A
authors.lastname: Zaghlool
authors.forename: M V Prasad
authors.initials: MV
authors.lastname: Linga Reddy
authors.forename: Elena
authors.initials: E
authors.lastname: Sanchez
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Bernardo A
authors.initials: BA
authors.lastname: Pons-Estel
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.forename: Nadia
authors.initials: N
authors.lastname: Barizzone
authors.forename: Nadia
authors.initials: N
authors.lastname: Barrizzone
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Danieli
authors.forename: Carmen
authors.initials: C
authors.lastname: Gutierrez
authors.forename: Ana
authors.initials: A
authors.lastname: Suarez
authors.forename: Peter
authors.initials: P
authors.lastname: Junker
authors.forename: Helle
authors.initials: H
authors.lastname: Laustrup
authors.forename: Maria Francisca
authors.initials: MF
authors.lastname: González-Escribano
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Hadi
authors.initials: H
authors.lastname: Abderrahim
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017089:Ankyrin Repeat / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002877:Chromosomes, Human; D015331:Cohort Studies; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005091:Exons; D017353:Gene Deletion; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006239:Haplotypes; D006639:Histidine / Q000378:metabolism; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D013548:Sweden / Q000453:epidemiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C447641:BANK1 protein, human; D018076:DNA, Complementary; D008565:Membrane Proteins; D020033:Protein Isoforms; D006639:Histidine