title: Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients.
abstract: Defence against Neisseria meningitidis involves complement-mediated bactericidal activity. Factor H (fH) down-regulates complement activation. A putatively functional single-nucleotide-polymorphism (SNP) exists within a presumed nuclear-factor-kappa-B responsive element (NF-kB) in the fH gene (C-496T). Genetic and functional investigations were carried out to determine whether C-496T has a role in meningococcal disease (MD) susceptibility. Genetic susceptibility was investigated in 2 independent studies, a case-control and family-based transmission-disequilibrium-test (TDT), using 2 separate cohorts of UK Caucasian patients. MD susceptibility was both genetically associated with the C/C homozygous genotype (OR = 2.0, 95% CI 1.3 - 3.2, p = 0.001) and linked to the C allele (p = 0.04), the association being most significant in serogroup C infected patients (OR = 2.9, 95% CI 1.6 - 5.5, p = 0.0002). FH serum concentrations were also associated with C-496T genotype, with highest fH concentrations in C/C homozygous individuals (p = 0.01). Functional studies showed NF-kappa-B binding to the C-496T-containing region and that pre-incubation of fH with meningococci reduced bactericidal activity and increased meningococci B and C survival in blood. This study shows that C-496T is both associated and linked with MD and that individuals possessing the fH C-496T C/C genotype are more likely to have increased serum fH protein levels, have reduced bactericidal activity against meningococci and be at an increased risk of contracting MD.
authors.affiliation: Department of Clinical and Molecular Genetics, Institute of Child Health, University College, London, UK. e.haralambous@ich.ucl.ac.uk
authors.forename: Elene
authors.initials: E
authors.lastname: Haralambous
authors.forename: Saoirse O
authors.initials: SO
authors.lastname: Dolly
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
authors.forename: David J
authors.initials: DJ
authors.lastname: Litt
authors.forename: Irina A
authors.initials: IA
authors.lastname: Udalova
authors.forename: Cliona
authors.initials: C
authors.lastname: O'dwyer
authors.forename: Paul R
authors.initials: PR
authors.lastname: Langford
authors.forename: J
authors.initials: J
authors.lastname: Simon Kroll
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001770:Blood Bactericidal Activity; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D017242:Complement Factor H / Q000032:analysis* / Q000235:genetics*; D004198:Disease Susceptibility; D005192:Family Health; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D008589:Meningococcal Infections / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D013223:Statistics as Topic; D006113:United Kingdom; D044465:White People
chemical_list: D016328:NF-kappa B; D017242:Complement Factor H