Osborne, A;
Breno, M;
Ghiringhelli Borsa, N;
Bu, F;
Frémeaux-Bacchi, V;
Gale, D;
van den Heuvel, LP;
... Perkins, SJ; + view all
(2018)
Statistical validation of rare complement variants provides insights on the molecular basis of atypical haemolytic uraemic syndrome and C3 glomerulopathy.
Journal of Immunology
, 200
(7)
pp. 2464-2478.
10.4049/jimmunol.1701695.
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Abstract
Atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and over-activation 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-centre 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 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 (ExAC) 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 ExAC (allele frequency <0.01%), thus correlating these with aHUS. For C3G, an association was only found for rare variants in C3 and the Nterminal C3b-binding or C-terminal non-surface-associated regions of CFH. In conclusion, the RV analyses showed non-random distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.
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