Variants in BANK1 are associated with lupus nephritis of European ancestry

Karin Bolin,Lars Rönnblom,Øyvind Molberg,Jonas Carlsson Almlöf,Andreas Jönsen,Christopher Sjöwall,Søren Jacobsen,Dag Leonard,Joanne Nititham,Iva Gunnarsson,Malena Loberg Haarhaus,Karoline Lerang,Anne Troldborg,Solbritt Rantapää‐Dahlqvist ,Anders Bengtsson ,Ann Christine Syvänen ,Anne Voß ,Juliana Imgenberg‐Kreuz ,Lindsey A Criswell ,Johanna K Sandling,Elisabet Svenungsson,Pascal Pucholt,Andrei Alexsson,Gunnel Nordmark

doi:10.1038/s41435-021-00142-8

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.

Highlights

Systemic lupus erythematosus (SLE) is a complex autoimmune disease predominantly affecting women in their child-bearing age
Genetic variants in HLA-DR, Integrin Subunit Alpha M (ITGAM), FCGR, IRF5, TNIP1, STAT4, and TNFSF4 have been associated with both SLE per se and with Lupus nephritis (LN), whereas APOL1, PDGFRA, and HAS2 have been identified in LN [6]
The strongest signals of association with LN were found for four highly-linked single nucleotide polymorphisms (SNPs) close to the Nuclear Factor of Kappa Light Polypeptide Gene Enhancer in B Cells Inhibitor, Alpha (NFKBIA) gene

Summary

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune disease predominantly affecting women in their child-bearing age. Lupus nephritis (LN) constitutes one of the main clinical challenges in patients with SLE and is a cause of significant morbidity and mortality. The genetic background to SLE has been thoroughly investigated through candidate gene and genome-wide association studies. Some of the known SLE susceptibility genes, which function in the immune system, seem to be associated with LN. Genetic variants in HLA-DR, ITGAM, FCGR, IRF5, TNIP1, STAT4, and TNFSF4 have been associated with both SLE per se and with LN, whereas APOL1, PDGFRA, and HAS2 have been identified in LN [6]. Genetic variants in STAT4 have been proposed to associate with SLE and LN in general, and with a more severe subtype of LN and renal failure [7, 8]

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Conclusion