{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T03:05:52Z","timestamp":1771902352080,"version":"3.50.1"},"reference-count":42,"publisher":"S. Karger AG","license":[{"start":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T00:00:00Z","timestamp":1678665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T00:00:00Z","timestamp":1678665600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Glomerular Dis"],"abstract":"<jats:p>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 &amp;lt; 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 &amp;lt; 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. <\/jats:p>","DOI":"10.1159\/000529959","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T22:00:36Z","timestamp":1677880836000},"page":"116-125","source":"Crossref","is-referenced-by-count":3,"title":["A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy"],"prefix":"10.1159","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1393-9282","authenticated-orcid":false,"given":"Sanjana","family":"Gupta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mallory Louise","family":"Downie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-2883","authenticated-orcid":false,"given":"Chris","family":"Cheshire","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Dufek-Kamperis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1333-9938","authenticated-orcid":false,"given":"Adam Paul","family":"Levine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-9919","authenticated-orcid":false,"given":"Paul","family":"Brenchley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elion","family":"Hoxha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolf","family":"Stahl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil","family":"Ashman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth 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Philip","family":"Gale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"127","published-online":{"date-parts":[[2023,3,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfq665"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2014.11.002"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810457"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409354"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012895"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2019.09.014"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020101395"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020081165"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2020.05.030"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2021.08.014"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2019.07.014"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2012.486"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2015.10.004"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfx296"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009742"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.05310513"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2012.11.004"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012080771"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15383-w"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2011.01.002"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.310"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1246949"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2205"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1038\/nature05911"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018101054"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.116"},{"key":"ref28","doi-asserted-by":"publisher","DOI":"10.1086\/521987"},{"key":"ref29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2021.02.025"},{"key":"ref30","doi-asserted-by":"publisher","DOI":"10.21105\/joss.00731"},{"key":"ref31","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012070730"},{"key":"ref32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108735"},{"key":"ref33","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2014.50"},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.1007\/s10157-014-1054-2"},{"key":"ref35","doi-asserted-by":"publisher","DOI":"10.1038\/srep08803"},{"key":"ref36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173201"},{"key":"ref37","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2016.01.030"},{"key":"ref38","doi-asserted-by":"publisher","DOI":"10.1309\/AJCP8QMOY5GLRSFP"},{"key":"ref39","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016060644"},{"key":"ref40","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2017111185"},{"key":"ref41","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216227"},{"key":"ref42","doi-asserted-by":"publisher","DOI":"10.1038\/jhh.2008.123"}],"container-title":["Glomerular 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