Variants in BANK1 are associated with lupus nephritis of European ancestry
Karin Bolin, Juliana Imgenberg‐Kreuz, Dag Leonard, Johanna K. Sandling, Andrei Alexsson, Pascal Pucholt, Malena Loberg Haarhaus, Jonas Carlsson Almlöf, Joanne Nititham, Andreas Jönsen, Christopher Sjöwall, Anders Bengtsson, Solbritt Rantapää‐Dahlqvist, Elisabet Svenungsson, Iva Gunnarsson, Ann-Christine Syvänen, Karoline Lerang, Anne Troldborg, Anne Voss, Øyvind Molberg, Søren Jacobsen, Lindsey A. Criswell, Lars Rönnblom, Gunnel Nordmark
Abstract
Abstract 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.