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Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy

Research output: Contribution to journalArticle

Adam P. Levine, Melanie M.y. Chan, Omid Sadeghi-alavijeh, Edwin K.s. Wong, H. Terence Cook, Sofie Ashford, Keren Carss, Martin T. Christian, Matthew Hall, Claire Louise Harris, Paul Mcalinden, Kevin J. Marchbank, Stephen D. Marks, Heather Maxwell, Karyn Megy, Christopher J. Penkett, Monika Mozere, Kathleen E. Stirrups, Salih Tuna, Julie Wessels & 5 more Deborah Whitehorn, Nihr Bioresource, Catherine Williamson, Sally A. Johnson, Daniel P. Gale

Original languageEnglish
Pages (from-to)365-373
Number of pages9
JournalJournal of the American Society of Nephrology
Issue number2
Early online date31 Jan 2020
Accepted/In press3 Nov 2019
E-pub ahead of print31 Jan 2020
PublishedFeb 2020

King's Authors


Background Primary 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. MethodsWe analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individualswithout the condition (controls) as part of theNational Institutes ofHealth Research 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 significant enrichment of rare variants 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=3.29×10 -8; 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, and DRB1*03:01 (P=1.21×10 -8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis ofHLA serotypes in 338 individuals withmembranoproliferativeGNand 15,614 individualswith 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 causing primary membranoproliferativeGNand implicate an underlying autoimmune mechanism inmost cases.

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