PT - JOURNAL ARTICLE AU - Casimiro Castillejo-López AU - Angélica M Delgado-Vega AU - Jerome Wojcik AU - Sergey V Kozyrev AU - Elangovan Thavathiru AU - Ying-Yu Wu AU - Elena Sánchez AU - David Pöllmann AU - Juan R López-Egido AU - Serena Fineschi AU - Nicolás Domínguez AU - Rufei Lu AU - Judith A James AU - Joan T Merrill AU - Jennifer A Kelly AU - Kenneth M Kaufman AU - Kathy L Moser AU - Gary Gilkeson AU - Johan Frostegård AU - Bernardo A Pons-Estel AU - Sandra D'Alfonso AU - Torsten Witte AU - José Luis Callejas AU - John B Harley AU - Patrick M Gaffney AU - Javier Martin AU - Joel M Guthridge AU - Marta E Alarcón-Riquelme TI - Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes <em>BANK1</em> and <em>BLK</em> AID - 10.1136/annrheumdis-2011-200085 DP - 2012 Jan 01 TA - Annals of the Rheumatic Diseases PG - 136--142 VI - 71 IP - 1 4099 - http://ard.bmj.com/content/71/1/136.short 4100 - http://ard.bmj.com/content/71/1/136.full SO - Ann Rheum Dis2012 Jan 01; 71 AB - 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.