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

Gupta, Sanjana; Downie, Mallory Lorraine; Cheshire, Chris; Dufek-Kamperis, Stephanie; Levine, Adam Paul; Brenchley, Paul; Hoxha, Elion; ... Gale, Daniel Philip; + view all (2023) A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy. Glomerular Diseases , 3 (1) pp. 116-125. 10.1159/000529959. Green open access

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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.

Type: Article
Title: A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.1159/000529959
Publisher version: http://doi.org/10.1159/000529959
Language: English
Additional information: © 2023 The Author(s). Published by S. Karger AG, Basel. This article is licensed under the Creative Commons AttributionNonCommercial 4.0 International License (CC BY-NC) (https://creativecommons.org/licenses/by-nc/4.0/) (http://www. karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.
Keywords: Autoantibody, Genetic risk score, Membranous nephropathy, Phospholipase A2 receptor 1, Thrombospondin type-1 domain containing 7A
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10169032
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