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

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Kumar, Vikrant, Pouw, Richard B, Autio, Matias I, Sagmeister, Manfred G, Phua, Zai Yang, Borghini, Lisa, Wright, Victoria J, Hoggart, Clive, Pan, Bangfen, Tan, Antson Kiat Yee et al (show 28 more authors) , Binder, Alexander, Brouwer, Mieke C, Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van Der Flier, Michiel, Reiter, Karl, Nöthen, Markus M, Hoffmann, Per, EUCLIDS consortium, , Schlapbach, Luregn J, Bellos, Evangelos, Anderson, Suzanne, Secka, Fatou, Martinón-Torres, Federico, Salas, Antonio, Fink, Colin, Carrol, Enitan D ORCID: 0000-0001-8357-7726, Pollard, Andrew J, Coin, Lachlan J, Zenz, Werner, Wouters, Diana, Ang, Lay Teng, Hibberd, Martin L, Levin, Michael, Kuijpers, Taco W and Davila, Sonia (2022) Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations. American journal of human genetics, 109 (9). S0002-9297(22)00318-4-S0002-9297(22)00318-4.

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Abstract

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^-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.

Item Type:	Article
Uncontrolled Keywords:	EUCLIDS consortium
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	02 Sep 2022 10:04
Last Modified:	18 Jan 2023 20:46
DOI:	10.1016/j.ajhg.2022.08.001
Open Access URL:	https://www.cell.com/ajhg/fulltext/S0002-9297(22)0...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3163164