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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2464-2478
Number of pages15
JournalJournal of Immunology
Volume200
Issue number7
DOIs
Publication statusPublished - Apr 1 2018

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Genes
Exome
Gene Frequency
Alternative Complement Pathway
Atypical Hemolytic Uremic Syndrome
Proteins
Genome
Databases
Phenotype
chemotactic factor inactivator

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Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy. / Osborne, Amy J; Breno, Matteo; Borsa, Nicolo Ghiringhelli; Bu, Fengxiao; Frémeaux-Bacchi, Véronique; Gale, Daniel P; van den Heuvel, Lambertus P; Kavanagh, David; Noris, Marina; Pinto, Sheila; Rallapalli, Pavithra M; Remuzzi, Giuseppe; Rodríguez de Cordoba, Santiago; Ruiz, Angela; Smith, Richard J H; Vieira-Martins, Paula; Volokhina, Elena; Wilson, Valerie; Goodship, Timothy H J; Perkins, Stephen J.

In: Journal of Immunology, Vol. 200, No. 7, 01.04.2018, p. 2464-2478.

Research output: Contribution to journalArticle

Osborne, AJ, Breno, M, Borsa, NG, Bu, F, Frémeaux-Bacchi, V, Gale, DP, van den Heuvel, LP, Kavanagh, D, Noris, M, Pinto, S, Rallapalli, PM, Remuzzi, G, Rodríguez de Cordoba, S, Ruiz, A, Smith, RJH, Vieira-Martins, P, Volokhina, E, Wilson, V, Goodship, THJ & Perkins, SJ 2018, 'Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy', Journal of Immunology, vol. 200, no. 7, pp. 2464-2478. https://doi.org/10.4049/jimmunol.1701695
Osborne, Amy J ; Breno, Matteo ; Borsa, Nicolo Ghiringhelli ; Bu, Fengxiao ; Frémeaux-Bacchi, Véronique ; Gale, Daniel P ; van den Heuvel, Lambertus P ; Kavanagh, David ; Noris, Marina ; Pinto, Sheila ; Rallapalli, Pavithra M ; Remuzzi, Giuseppe ; Rodríguez de Cordoba, Santiago ; Ruiz, Angela ; Smith, Richard J H ; Vieira-Martins, Paula ; Volokhina, Elena ; Wilson, Valerie ; Goodship, Timothy H J ; Perkins, Stephen J. / Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy. In: Journal of Immunology. 2018 ; Vol. 200, No. 7. pp. 2464-2478.
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T1 - Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

AU - Osborne, Amy J

AU - Breno, Matteo

AU - Borsa, Nicolo Ghiringhelli

AU - Bu, Fengxiao

AU - Frémeaux-Bacchi, Véronique

AU - Gale, Daniel P

AU - van den Heuvel, Lambertus P

AU - Kavanagh, David

AU - Noris, Marina

AU - Pinto, Sheila

AU - Rallapalli, Pavithra M

AU - Remuzzi, Giuseppe

AU - Rodríguez de Cordoba, Santiago

AU - Ruiz, Angela

AU - Smith, Richard J H

AU - Vieira-Martins, Paula

AU - Volokhina, Elena

AU - Wilson, Valerie

AU - Goodship, Timothy H J

AU - Perkins, Stephen J

N1 - Copyright © 2018 by The American Association of Immunologists, Inc.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

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