Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients.

Journal article

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: Haralambous, E; Dolly, S; Hibberd, M; Litt, D; Udalova, I

• Publication status: Published
• Journal: Scandinavian journal of infectious diseases
• Volume: 38
• Issue: 9
• Pages: 764-771
• Publication date: 2006-01-01
• DOI: 10.1080/00365540600643203
• EISSN: 1651-1980
• ISSN: 0036-5548
• Language: English
• Keywords: Adolescent; Blood Bactericidal Activity; Meningococcal Infections; Homozygote; Adult; Middle Aged; NF-kappa B; Alleles; Great Britain; Protein Binding; Polymorphism, Single Nucleotide; Family Health; Child; Infant; Cohort Studies; Child, Preschool; Case-Control Studies; Humans; Statistics as Topic; Complement Factor H; Aged; Disease Susceptibility; Genetic Predisposition to Disease; European Continental Ancestry Group