BACKGROUND: BANK1 and BLK belong to the pleiotropic autoimmune genes; recently, 
epistasis between BANK1 and BLK was detected in systemic lupus erythematosus. 
Although BLK has been reproducibly identified as a risk factor in rheumatoid 
arthritis (RA), reports are conflicting about the contribution of BANK1 to RA 
susceptibility. To ascertain the real impact of BANK1 on RA genetic 
susceptibility, we performed a large meta-analysis including our original data 
and tested for an epistatic interaction between BANK1 and BLK in RA 
susceptibility.
PATIENTS AND METHODS: We investigated data for 1,915 RA patients and 1,915 
ethnically matched healthy controls genotyped for BANK1 rs10516487 and rs3733197 
and BLK rs13277113. The association of each SNP and RA was tested by logistic 
regression. Multivariate analysis was then used with an interaction term to test 
for an epistatic interaction between the SNPs in the 2 genes.
RESULTS: None of the SNPs tested individually was significantly associated with 
RA in the genotyped samples. However, we detected an epistatic interaction 
between BANK1 rs3733197 and BLK rs13277113 (P(interaction)  = 0.037). In 
individuals carrying the BLK rs13277113 GG genotype, presence of the BANK1 
rs3733197 G allele increased the risk of RA (odds ratio 1.21 [95% confidence 
interval 1.04-1.41], P = 0.015. Combining our results with those of all other 
studies in a large trans-ethnic meta-analysis revealed an association of the 
BANK1 rs3733197 G allele and RA (1.11 [1.02-1.21], P = 0.012).
CONCLUSION: This study confirms BANK1 as an RA susceptibility gene and for the 
first time provides evidence for epistasis between BANK1 and BLK in RA. Our 
results illustrate the concept of pleiotropic epistatic interaction, suggesting 
that BANK1 and BLK might play a role in RA pathogenesis.