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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
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; Nöthen, MM; Hoffmann, P; Schlapbach, LJ; Bellos, E; Anderson, S; Secka, F; Martinón-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, , EUCLIDS, consortium.
Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.
Am J Hum Genet. 2022; 109(9): 1680-1691.
Doi: 10.1016/j.ajhg.2022.08.001
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- Leading authors Med Uni Graz
- Sagmeister Manfred Gerald
- Co-authors Med Uni Graz
- Binder Alexander
- Zenz Werner
- Study Group Members Med Uni Graz:
- Kohlfürst Daniela
- Müller Martin
- Pfurtscheller Klaus
- Roedl Siegfried
- Walcher Wolfgang
- Zobel Gerfried
- Zöhrer Bettina
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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.
- Find related publications in this database (using NLM MeSH Indexing)
- Blood Proteins - genetics
- Complement Factor H - genetics
- Complement System Proteins - genetics
- Genetic Predisposition to Disease - administration & dosage
- Genotype - administration & dosage
- Humans - administration & dosage
- Meningococcal Infections - genetics