BANK1 – Systemic Lupus Erythematosus

Common and rare variants in BANK1 have been implicated as susceptibility factors for systemic lupus erythematosus (SLE). In a genome-wide scan of 85,042 SNPs, a nonsynonymous substitution in BANK1 (c.182G>A (p.Arg61His)) showed strong association with SLE across four independent European-derived case-control cohorts (combined P = 3.7×10⁻¹⁰; OR = 1.38) (PMID:18204447). This finding was replicated in 1,892 cases and 2,652 controls, confirming associations at rs17266594 and rs10516487 (OR = 1.22) (PMID:19339986). A meta-analysis of over 12,000 SLE subjects and 19,000 controls further reinforced the contribution of BANK1 polymorphisms rs17266594, rs10516487, and rs3733197 to disease risk (P ≤ 1.97×10⁻⁵; OR ≤ 1.38) (PMID:21208380). Despite consistent replication, no segregation in familial pedigrees or de novo mutations have been reported.

Functional studies demonstrate that the risk allele at rs10516487 (R61H) enhances exon 2 inclusion, alters protein multimerization, and perturbs B-cell receptor (BCR) calcium signaling (PMID:21900951). Additional assays of TLR7-stimulated B cells reveal that BANK1 variants modulate STAT1 activation, IRF7 nuclear translocation, and IgG production in murine lupus models (PMID:27228057, PMID:27816669). Conversely, BANK1 loci were not associated with primary antiphospholipid syndrome (PMID:19644876) or giant cell arteritis, underscoring disease-specific effects. Key take-home: BANK1 variants confer modest but reproducible SLE risk through dysregulated B-cell signaling, with potential for stratified risk assessment.

References

• Nature genetics • 2008 • Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus PMID:18204447
• Genes and immunity • 2009 • Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-derived population PMID:19339986
• International journal of immunogenetics • 2011 • The association between BANK1 and TNFAIP3 gene polymorphisms and systemic lupus erythematosus: a meta-analysis PMID:21208380
• Genes and immunity • 2012 • The dual effect of the lupus-associated polymorphism rs10516487 on BANK1 gene expression and protein localization PMID:21900951
• PloS one • 2016 • BANK1 Regulates IgG Production in a Lupus Model by Controlling TLR7-Dependent STAT1 Activation PMID:27228057
• Clinical immunology • 2016 • The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans PMID:27816669
• Arthritis and rheumatism • 2009 • Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome PMID:19644876

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