Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus.
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.
Kozyrev
Sergey V
SV
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden.
Abelson
Anna-Karin
AK
Wojcik
Jerome
J
Zaghlool
Ammar
A
Linga Reddy
M V Prasad
MV
Sanchez
Elena
E
Gunnarsson
Iva
I
Svenungsson
Elisabet
E
Sturfelt
Gunnar
G
Jönsen
Andreas
A
Truedsson
Lennart
L
Pons-Estel
Bernardo A
BA
Witte
Torsten
T
D'Alfonso
Sandra
S
Barizzone
Nadia
N
Barrizzone
Nadia
N
Danieli
Maria Giovanna
MG
Gutierrez
Carmen
C
Suarez
Ana
A
Junker
Peter
P
Laustrup
Helle
H
González-Escribano
Maria Francisca
MF
Martin
Javier
J
Abderrahim
Hadi
H
Alarcón-Riquelme
Marta E
ME
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
D048868:Adaptor Proteins, Signal Transducing; C447641:BANK1 protein, human; D018076:DNA, Complementary; D008565:Membrane Proteins; D020033:Protein Isoforms; D006639:Histidine