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

American journal of human genetics

Authors: Vikrant Kumar, Richard B Pouw, Matias I Autio, Manfred G Sagmeister, Zai Yang Phua, Lisa Borghini, Victoria J Wright, Clive Hoggart, Bangfen Pan, Antson Kiat Yee Tan, Alexander Binder, Mieke C Brouwer, Ellie Pinnock, Ronald De Groot, Jan Hazelzet, Marieke Emonts, Michiel Van Der Flier, Karl Reiter, Markus M Nöthen, Per Hoffmann, Luregn J Schlapbach, Evangelos Bellos, Suzanne Anderson, Fatou Secka, Federico Martinón-Torres, Antonio Salas, Colin Fink, Enitan D Carrol, Andrew J Pollard, Lachlan J Coin, Werner Zenz, Diana Wouters, Lay Teng Ang, Martin L Hibberd, Michael Levin, Taco W Kuijpers, Sonia Davila

Neisseria 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) by decreasing the concentration of FH in the blood (p value = 1.4 × 10). 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.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 36007525

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