Functional Variants in the B-cell Gene BANK1 Are Associated With Systemic Lupus Erythematosus

Nat Genet. 2008 Feb;40(2):211-6. doi: 10.1038/ng.79. Epub 2008 Jan 20.

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Alleles
  • Alternative Splicing
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Ankyrin Repeat / genetics
  • B-Lymphocytes / metabolism*
  • Case-Control Studies
  • Chromosomes, Human
  • Cohort Studies
  • DNA, Complementary / analysis
  • DNA, Complementary / genetics
  • Exons
  • Gene Deletion
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome, Human
  • Haplotypes
  • Histidine / metabolism
  • Humans
  • Introns
  • Linkage Disequilibrium
  • Logistic Models
  • Lupus Erythematosus, Systemic / epidemiology
  • Lupus Erythematosus, Systemic / etiology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / metabolism*
  • Lupus Erythematosus, Systemic / pathology
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Physical Chromosome Mapping
  • Polymorphism, Single Nucleotide
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Sequence Analysis, DNA
  • Sweden / epidemiology

Substances

  • Adaptor Proteins, Signal Transducing
  • BANK1 protein, human
  • DNA, Complementary
  • Membrane Proteins
  • Protein Isoforms
  • Histidine

Associated data

  • GENBANK/AB063170
  • GENBANK/EU051376
  • GENBANK/EU051377
  • GENBANK/EU051378
  • RefSeq/NM_017935