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Lookup NU author(s): Dr Edwin Wong, Professor Claire Harris, Professor Kevin MarchbankORCiD, Dr Sally Johnson
This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society of Nephrology, 2020.
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ABSTRACT BackgroundPrimary membranoproliferative GN, including complement 3(C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. MethodsWeanalyzedwhole-genomesequencedatafrom165primarymembranoproliferativeGNcases and10,250individualswithoutthecondition(controls)aspartoftheNationalInstitutesofHealthResearch BioResource–Rare Diseases Study. We examined copy number, rare, and common variants. Results Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significantenrichment of rarevariants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.2931028; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01,andDRB1*03:01(P=1.2131028;OR,2.19;95%CI,1.66to2.89).This findingwasreplicated byanalysisofHLAserotypesin338individualswithmembranoproliferativeGNand15,614individualswith nonimmune renal failure. Conclusions We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causingprimarymembranoproliferativeGNandimplicateanunderlyingautoimmunemechanisminmostcases
Author(s): Levine AP, Chan MMY, Sadeghi-Alavijeh O, Wong EKS, Cook HT, Ashford S, Carss k, Christian MT, Hall M, Harris C, McAlinden P, Marchbank KJ, Marks SD, Maxwell H, Megy K, Penkett CJ, Mozere M, Stirrups KE, Tuna S, Wessels J, Whitehorn D, Johnson SA, Gale DP
Publication type: Article
Publication status: Published
Journal: Journal of the American Society of Nephrology
Year: 2020
Volume: 31
Issue: 1
Print publication date: 01/01/2020
Online publication date: 10/01/2020
Acceptance date: 03/11/2019
Date deposited: 10/01/2020
ISSN (print): 1046-6673
ISSN (electronic): 1533-3450
Publisher: American Society of Nephrology
URL: https://doi.org/10.1681/ASN.2019040433
DOI: 10.1681/ASN.2019040433
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