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.

Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

“…Factor H (fH) regulates the alternative pathway by inactivating C3bBb (12). The fH -496C/C genotype was found to be associated with meningococcal disease (OR, 2.0; 95% CI, 1.3-3.2) (17). Most of the candidate gene approach studies lacked power to detect true associations (11).…”

Genetic variation of innate immune response genes in invasive pneumococcal and meningococcal disease applied to the pathogenesis of meningitis

“…CFH is responsible for downregulation of complement activation and polymorphisms in CFH are independently associated with MD. Individuals with the C496T CC genotype have increased levels of CFH and have reduced bactericidal activity against meningococci, 38 thus predisposing for MM. All together we were able to summarize the literature on SNPs that affect the susceptibility to IPD and IMD.…”

“…22 A higher incidence of infections with encapsulated bacteria, especially meningococci, is observed in people with deficiencies in all three pathways (the classical, the alternative and the lectin-mediated pathway) of the complement system. [36][37][38][39] C-reactive protein binds specifically to ChoP of SP and next, interacts with complement component C1q to activate the classical pathway of complement. 22 Pneumococcal surface protein (Psp) A and PspC are involved in the inhibition of complement activation by interfering binding of SP with complement factor C3 (classical pathway) and factor H (alternative pathway) respectively.…”

“…The À496C/C genotype was significantly associated with meningococcal infection. 38 Recently, Davila et al…”

Clinical and Epidemiological Differences Among Meningococcal C Conjugate Vaccine Failures and Non-Vaccinated Cases

“…The role of individual susceptibility and the presence of risk factors for the disease have been also widely studied. The presence of some immunodeficiencies [7,11,[19][20][21], special determinants in the host [22], tobacco consumption [23,24] and coinfections with another respiratory diseases [25][26][27][28], among others factors, have been associated to the meningococcal disease.…”