Variants in BANK1 are associated with lupus nephritis of European ancestry

The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN ( p < 1 × 10 −4 , NFKBIA, CACNA1S , ITGA1 , BANK1, OR2Y, and ACER3 ) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 ( p = 9.5 × 10 −4 ) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 ( p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened ( p = 2.2 × 10 −7 ). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.