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Lookup NU author(s): Professor Marieke Emonts-le ClercqORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2022 The AuthorsNeisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10−16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10−11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.
Author(s): Kumar V, Pouw RB, Autio MI, Sagmeister MG, Phua ZY, Borghini L, Wright VJ, Hoggart C, Pan B, Tan AKY, Binder A, Brouwer MC, Pinnock E, De Groot R, Hazelzet J, Emonts M, Van Der Flier M, Reiter K, Nothen MM, Hoffmann P, Schlapbach LJ, Bellos E, Anderson S, Secka F, Martinon-Torres F, Salas A, Fink C, Carrol ED, Pollard AJ, Coin LJ, Zenz W, Wouters D, Ang LT, Hibberd ML, Levin M, Kuijpers TW, Davila S
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2022
Volume: 109
Issue: 9
Pages: 1680-1691
Print publication date: 01/09/2022
Online publication date: 24/08/2022
Acceptance date: 31/07/2022
Date deposited: 13/10/2022
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2022.08.001
DOI: 10.1016/j.ajhg.2022.08.001
PubMed id: 36007525
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