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.

Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome

“…Statistical analyses were performed using UNPHASED version 3.0.13 software (Frank Dudbridge, MRC Biostatistics Unit, Cambridge, UK), and ORs were calculated using PLINK version 1.05 software (free Software Foundation, Boston, MA). Power was calculated with Quanto version 1.2.3 software (Jim Gauderman and John Morrison, University of Southern California, Los Angeles, CA) at a level of significance of ␣ ϭ 0.05, under an additive model for the OR previously identified for SLE (4,11,12,14) and the allelic frequencies in control subjects given an approximate disease prevalence of 0.0005.…”

“…Of those, particularly IRF5 (4-7) and STAT4 (5,(8)(9)(10) have been confirmed in several studies and are clearly associated with lupus. For BLK and BANK1, replication studies are under way (11,12). In lupus, IRF5 displays an allelic odds ratio (OR) of 1.67, while STAT4 has an OR of 1.54, BLK an OR of 1.39, and BANK1 an OR of 1.38.…”

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

“…[1][2][3][4] Interestingly, several of these T1D susceptibility loci are shared with other immune-mediated diseases, namely PTPN22, CTLA4, IL2RA, IL2, IL7R and SH2B3 (see Table 1 for full gene names). 1,5,6 Therefore, we sought to test newly identified rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis (AS) and Crohn's disease (CD) loci for association in T1D [7][8][9][10][11][12][13][14][15][16][17] with the assumption of an increased prior probability of association based on the previous evidence of overlapping risk alleles across autoimmune diseases. 18 We selected single nucleotide polymorphisms (SNPs) for genotyping that had shown a convincing evidence of association with at least one other autoimmune disease from genome-wide association scans published over the past 2 years.…”

“…18 We selected single nucleotide polymorphisms (SNPs) for genotyping that had shown a convincing evidence of association with at least one other autoimmune disease from genome-wide association scans published over the past 2 years. We genotyped SNPs from the genes: CD58 (rs12044852) which has been associated with multiple sclerosis; 8 STAT3 (rs3816769) which has been associated with CD; 7 IL1A (rs17561) and ERAP1, previously called ARTS1 (rs30187) which have been associated with AS; 15,17 MMEL1-TNFRSF14 (rs3890745), CDK6 (rs42041), the 7q23 gene desert (rs11761231), CCL21 (rs2812378), TRAF1/C5 (rs3761847), KIF5A(rs1678542) and CD40 (rs4810485), which have been associated with RA; 7,12,19 BANK1 (rs10516487), FAM167A previously called C8orf13 (rs13277113) and ITGAM (rs9888739) which have been associated with SLE [9][10][11]20 and STAT4 (rs7574865) and TNFAIP3 (rs6920220 and rs10499194) which have been associated with both RA and SLE 13,14,16,21,22 (See Table 1 for full gene names).…”

X Inactivation, Female Mosaicism, and Sex Differences in Renal Diseases

“…44,47 Conceivably, some X-linked gene plays a significant role in the pathway leading to manifestations of the disease, as a good number of them are needed for normal immune homeostasis. Yet, among possible candidates that affect B cells identified by microchip analysis of single nucleotide polymorphisms (SNPs), 48 none so far can explain the sex difference in susceptibility. Possibly, a relevant gene is imprinted such that it has an effect only when inherited by a female.…”