TY - JOUR
T1 - Variants in BANK1 are associated with lupus nephritis of European ancestry
AU - Bolin, Karin
AU - Imgenberg-Kreuz, Juliana
AU - Leonard, Dag
AU - Sandling, Johanna K
AU - Alexsson, Andrei
AU - Pucholt, Pascal
AU - Haarhaus, Malena Loberg
AU - Almlöf, Jonas Carlsson
AU - Nititham, Joanne
AU - Jönsen, Andreas
AU - Sjöwall, Christopher
AU - Bengtsson, Anders A
AU - Rantapää-Dahlqvist, Solbritt
AU - Svenungsson, Elisabet
AU - Gunnarsson, Iva
AU - Syvänen, Ann-Christine
AU - Lerang, Karoline
AU - Troldborg, Anne
AU - Voss, Anne
AU - Molberg, Øyvind
AU - Jacobsen, Søren
AU - Criswell, Lindsey
AU - Rönnblom, Lars
AU - Nordmark, Gunnel
N1 - © 2021. The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Cohort Studies
KW - DNA Methylation
KW - Gene Expression Regulation
KW - Genotype
KW - Humans
KW - Lupus Erythematosus, Systemic
KW - Lupus Nephritis/genetics
KW - Membrane Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85107861880&partnerID=8YFLogxK
U2 - 10.1038/s41435-021-00142-8
DO - 10.1038/s41435-021-00142-8
M3 - Journal article
C2 - 34127828
SN - 1466-4879
VL - 22
SP - 194
EP - 202
JO - Genes and Immunity
JF - Genes and Immunity
IS - 3
ER -