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

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.

SUBMITTER: Kumar V

PROVIDER: S-EPMC9502058 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Kumar Vikrant V Pouw Richard B RB Autio Matias I MI Sagmeister Manfred G MG Phua Zai Yang ZY Borghini Lisa L Wright Victoria J VJ Hoggart Clive C Pan Bangfen B Tan Antson Kiat Yee AKY Binder Alexander A Brouwer Mieke C MC Pinnock Ellie E De Groot Ronald R Hazelzet Jan J Emonts Marieke M Van Der Flier Michiel M Reiter Karl K Nöthen Markus M MM Hoffmann Per P Schlapbach Luregn J LJ Bellos Evangelos E Anderson Suzanne S Secka Fatou F Martinón-Torres Federico F Salas Antonio A Fink Colin C Carrol Enitan D ED Pollard Andrew J AJ Coin Lachlan J LJ Zenz Werner W Wouters Diana D Ang Lay Teng LT Hibberd Martin L ML Levin Michael M Kuijpers Taco W TW Davila Sonia S

American journal of human genetics 20220824 9

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 control ...[more]

PMID: 36007525

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Project description:BackgroundNeisseria meningitidis can cause severe infection in humans. Polymorphism of Complement Factor H (CFH) is associated with altered risk of invasive meningococcal disease (IMD). We aimed to find whether polymorphism of other complement genes altered risk and whether variation of N. meningitidis factor H binding protein (fHBP) affected the risk association.MethodsWe undertook a case-control study with 309 European cases and 5,200 1958 Birth Cohort and National Blood Service cohort controls. We used additive model logistic regression, accepting P<0.05 as significant after correction for multiple testing. The effects of fHBP subfamily on the age at infection and severity of disease was tested using the independent samples median test and Student's T test. The effect of CFH polymorphism on the N. meningitidis fHBP subfamily was investigated by logistic regression and Chi squared test.ResultsRs12085435 A in C8B was associated with odds ratio (OR) of IMD (0.35 [95% CI 0.19-0.67]; P = 0.03 after correction). A CFH haplotype tagged by rs3753396 G was associated with IMD (OR 0.56 [95% CI 0.42-0.76], P = 1.6x10⁻⁴). There was no bacterial load (CtrA cycle threshold) difference associated with carriage of this haplotype. Host CFH haplotype and meningococcal fHBP subfamily were not associated. Individuals infected with meningococci expressing subfamily A fHBP were younger than those with subfamily B fHBP meningococci (median 1 vs 2 years; P = 0.025).DiscussionThe protective CFH haplotype alters odds of IMD without affecting bacterial load for affected heterozygotes. CFH haplotype did not affect the likelihood of infecting meningococci having either fHBP subfamily. The association between C8B rs12085435 and IMD requires independent replication. The CFH association is of interest because it is independent of known functional polymorphisms in CFH. As fHBP-containing vaccines are now in use, relationships between CFH polymorphism and vaccine effectiveness and side-effects may become important.

Project description:Key messageGenetic control of maize grain carotenoid profiles is coordinated through several loci distributed throughout three secondary metabolic pathways, most of which exhibit additive, and more importantly, pleiotropic effects. The genetic basis for the variation in maize grain carotenoid concentrations was investigated in two F2:3 populations, DEexp × CI7 and A619 × SC55, derived from high total carotenoid and high ?-carotene inbred lines. A comparison of grain carotenoid concentrations from population DEexp × CI7 grown in different environments revealed significantly higher concentrations and greater trait variation in samples harvested from a subtropical environment relative to those from a temperate environment. Genotype by environment interactions was significant for most carotenoid traits. Using phenotypic data in additive, environment-specific genetic models, quantitative trait loci (QTL) were identified for absolute and derived carotenoid traits in each population, including those specific to the isomerization of ?-carotene. A multivariate approach for these correlated traits was taken, using carotenoid trait principal components (PCs) that jointly accounted for 97 % or more of trait variation. Component loadings for carotenoid PCs were interpreted in the context of known substrate-product relationships within the carotenoid pathway. Importantly, QTL for univariate and multivariate traits were found to cluster in close proximity to map locations of loci involved in methyl-erythritol, isoprenoid and carotenoid metabolism. Several of these genes, including lycopene epsilon cyclase, carotenoid cleavage dioxygenase1 and beta-carotene hydroxylase, were mapped in the segregating populations. These loci exhibited pleiotropic effects on ?-branch carotenoids, total carotenoid profile and ?-branch carotenoids, respectively. Our results confirm that several QTL are involved in the modification of carotenoid profiles, and suggest genetic targets that could be used for the improvement of total carotenoid and ?-carotene in future breeding populations.

Dataset Information

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

Publications

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

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