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

Author

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, 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, Pollard, Andrew J, Coin, Lachlan J, Zenz, Werner, Wouters, Diana, Ang, Lay Teng, Hibberd, Martin L, Levin, Michael, Kuijpers, Taco W, Davila, Sonia, consortium, EUCLIDS, Pediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory, and ARD - Amsterdam Reproduction and Development

Subjects
CFHR3, Genotype, Meningococcal disease, infectious disease, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Complement, in-depth sequencing, Blood Proteins, Complement System Proteins, Neisseria meningitidis, factor H, QR, Meningococcal Infections, Factor H-related protein, genotyping, Complement Factor H, Genetics, Humans, CFH, Genetic Predisposition to Disease, Genetics (clinical), RC
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.

Published
2022

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