Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy.

Abstract

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (CFH, CFI, CD46, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFP, PLG, DGKE, and THBD) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes CFH, CFI, CD46, C3, and DGKE than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in C3 and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of CFH In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.

• Authors: Amy J Osborne, Matteo Breno, Nicolo Ghiringhelli Borsa, Fengxiao Bu, Véronique Frémeaux-Bacchi, Daniel P Gale, Lambertus P van den Heuvel, David Kavanagh, Marina Noris, Sheila Pinto, Pavithra M Rallapalli, Giuseppe Remuzzi, Santiago Rodríguez de Cordoba, Angela Ruiz, Richard J H Smith, Paula Vieira-Martins, Elena Volokhina, Valerie Wilson, Timothy H J Goodship, Stephen J Perkins
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 200 Issue 7 Pg. 2464-2478 (04 01 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29500241 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Complement C3
• Complement Factor H

Topics

• Atypical Hemolytic Uremic Syndrome (genetics, pathology)
• Complement C3 (genetics, metabolism)
• Complement Factor H (genetics)
• Complement Pathway, Alternative (genetics, physiology)
• Female
• Gene Frequency (genetics)
• Genetic Predisposition to Disease (genetics)
• Glomerulonephritis, Membranoproliferative (genetics, pathology)
• Humans
• Male
• Mutation, Missense (genetics)