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 language | English |
|---|---|
| Pages (from-to) | 2464-2478 |
| Number of pages | 15 |
| Journal | Journal of Immunology |
| Volume | 200 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Apr 1 2018 |
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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 journal › Article
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TY - JOUR
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.
AB - 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.
U2 - 10.4049/jimmunol.1701695
DO - 10.4049/jimmunol.1701695
M3 - Article
C2 - 29500241
VL - 200
SP - 2464
EP - 2478
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -