Journal Article

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

Linga Reddy, M V Prasad, Pons-Estel, Bernardo A, González-Escribano, Maria Francisca, Abelson, Anna-Karin, Sanchez, Elena, Barizzone, Nadia, Laustrup, Helle, Martin, Javier, D'Alfonso, Sandra, Witte, Torsten, Kozyrev, Sergey V, Sturfelt, Gunnar, Gutierrez, Carmen, Svenungsson, Elisabet, Danieli, Maria Giovanna, Suarez, Ana, Junker, Peter, Abderrahim, Hadi, Zaghlool, Ammar, Jönsen, Andreas, Alarcón-Riquelme, Marta E, Wojcik, Jerome, Gunnarsson, Iva, Truedsson, Lennart

2008

Overview

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance 1 , 2 , 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 × 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Agriculture / Alleles / Alternative Splicing / Amino Acid Motifs / Amino Acid Sequence / Amino Acid Substitution / Animal Genetics and Genomics / Ankyrin Repeat - genetics / Autoimmune diseases / B cells / B-Lymphocytes - metabolism / Basic Medicine / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Case-Control Studies / Chromosomes, Human / Clinical Medicine / Cohort Studies / DNA, Complementary - analysis / DNA, Complementary - genetics / Exons / Fundamental and applied biological sciences. Psychology / Gene Deletion / Gene Frequency / Gene Function / Genetic aspects / Genetic Predisposition to Disease / Genetic Variation / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genome, Human / Haplotypes / Histidine - metabolism / Human Genetics / Humans / Immunologi inom det medicinska området (Här ingår: Cell- och immunterapi) / Immunology in the Medical Area (including Cell and Immunotherapy) / Introns / Klinisk medicin / letter / Linkage Disequilibrium / Logistic Models / Lupus / Lupus Erythematosus, Systemic - epidemiology / Lupus Erythematosus, Systemic - etiology / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - metabolism / Lupus Erythematosus, Systemic - pathology / Medical and Health Sciences / Medical sciences / MEDICIN / Medicin och hälsovetenskap / MEDICINE / Medicinska och farmaceutiska grundvetenskaper / Membrane Proteins - genetics / Membrane Proteins - metabolism / Microbiology in the Medical Area / Mikrobiologi inom det medicinska området / Molecular Sequence Data / Physical Chromosome Mapping / Physiological aspects / Polymorphism, Single Nucleotide / Protein Isoforms - chemistry / Protein Isoforms - genetics / Protein Isoforms - metabolism / Protein Structure, Tertiary / Proteins / Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis / Sequence Analysis, DNA / Single nucleotide polymorphisms / Sweden - epidemiology / Systemic lupus erythematosus