OBJECTIVES: Altered signalling in B cells is a predominant feature of systemic 
lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as 
associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein 
involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase 
with important roles in B-cell development. To characterise the role of BANK1 
and BLK in SLE, a genetic interaction analysis was performed hypothesising that 
genetic interactions could reveal functional pathways relevant to disease 
pathogenesis.
METHODS: The GPAT16 method was used to analyse the gene-gene interactions of 
BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and 
immunoprecipitation was used to verify the physical interaction of BANK1 and 
BLK.
RESULTS: Epistatic interactions between BANK1 and BLK polymorphisms associated 
with SLE were observed in a discovery set of 279 patients and 515 controls from 
northern Europe. A meta-analysis with 4399 European individuals confirmed the 
genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding 
partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could 
also show a protein-protein interaction was tested. The co-immunoprecipitation 
and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and 
primary naive B cells endogenous binding was enhanced upon B-cell receptor 
stimulation using anti-IgM antibodies.
CONCLUSION: This study shows a genetic interaction between BANK1 and BLK, and 
demonstrates that these molecules interact physically. The results have 
important consequences for the understanding of SLE and other autoimmune 
diseases and identify a potential new signalling pathway.