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Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Lookup NU author(s): Professor Marieke Emonts-le ClercqORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
Agency for Science, Technology, and Research of Singapore (A∗STAR)
EUCLIDS Grant Agreement no. 279185

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