A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

Sanjana Gupta; Mallory Lorraine Downie; Chris Cheshire; Stephanie Dufek-Kamperis; Adam Paul Levine; Paul Brenchley; Elion Hoxha; Rolf Stahl; Neil Ashman; Ruth Jennifer Pepper; Sean Mason; Jill Norman; Detlef Bockenhauer; Horia Constantin Stanescu; Robert Kleta; Daniel Philip Gale

doi:10.1159/000529959

A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

Glomerular Dis. 2023 Mar 13;3(1):116-125. doi: 10.1159/000529959. eCollection 2023 Jan-Dec.

Authors

Sanjana Gupta¹, Mallory Lorraine Downie¹, Chris Cheshire¹, Stephanie Dufek-Kamperis¹, Adam Paul Levine^{1

2}, Paul Brenchley³, Elion Hoxha⁴, Rolf Stahl⁴, Neil Ashman⁵, Ruth Jennifer Pepper¹, Sean Mason⁶, Jill Norman¹, Detlef Bockenhauer¹, Horia Constantin Stanescu¹, Robert Kleta¹, Daniel Philip Gale¹

Affiliations

¹ UCL Department of Renal Medicine, University College London, London, UK.
² Research Department of Pathology, University College London, London, UK.
³ Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
⁴ Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Department of Renal Medicine, Barts Health, London, UK.
⁶ UCB Pharma, Slough, UK.

Abstract

Introduction: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans, genetic variation in at least five loci, PLA2R1, HLA-DRB1, HLA-DQA1, IRF4, and NFKB1, affects the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states.

Methods: 1,409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilizing the previously identified European MN loci, and results were compared with 4,929 healthy controls and 422 individuals with steroid-sensitive nephrotic syndrome.

Results: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody-positive (N = 372) compared with both the unaffected control (N = 4,929) and anti-THSD7A-positive (N = 31) groups (p < 0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1-positive patients, GRS was inversely correlated with age of disease onset (p = 0.009). Further, the GRS in the dual antibody-negative group (N = 355) was intermediate between controls and the PLA2R1-positive group (p < 0.0001).

Conclusion: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody-associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody-negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1.

Keywords: Autoantibody; Genetic risk score; Membranous nephropathy; Phospholipase A2 receptor 1; Thrombospondin type-1 domain containing 7A.

Grants and funding

Sanjana Gupta acknowledges support from UCB Pharma for her PhD funding. Paul Brenchley acknowledges support from MRC Project Grant MR/J010847/1 and from the Manchester Academic Healthcare Science Centre (MAHSC) (186/200). Daniel Philip Gale is supported by the St Peter’s Trust for Kidney, Bladder and Prostate Research. Elion Hoxha was supported by a grant from the Deutsche Forschungsgemeinschaft as part of the Sonderforschungsbereich 1192 (project B1 and C1), and the Heisenberg Programme. All these sources did not contribute directly to the data or manuscript but paid for the researchers’ time.