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.
%0 Journal Article
%1 haralambous_factor_2006
%A Haralambous, Elene
%A Dolly, Saoirse O
%A Hibberd, Martin L
%A Litt, David J
%A Udalova, Irina A
%A O'dwyer, Cliona
%A Langford, Paul R
%A Kroll, J Simon
%A Levin, Michael
%D 2006
%J Scandinavian Journal of Infectious Diseases
%K Activity, Adolescent, Adult, Aged, Alleles, Ancestry B, Bactericidal Binding, Blood Britain, Child, Cohort Complement Continental Disease Disease, European Factor Family Genetic Great Group, H, Health, Homozygote, Humans, Infant, Infections, Meningococcal Middle Nucleotide, Polymorphism, Predisposition Preschool, Protein Single Statistics Studies, Susceptibility, Topic as to {Case-Control} {NF-kappa}
%N 9
%P 764--71
%R 10.1080/00365540600643203
%T Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients
%U http://www.ncbi.nlm.nih.gov/pubmed/16938729
%V 38
%X 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.
@article{haralambous_factor_2006,
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.}},
added-at = {2011-03-11T10:05:34.000+0100},
author = {Haralambous, Elene and Dolly, Saoirse O and Hibberd, Martin L and Litt, David J and Udalova, Irina A and O'dwyer, Cliona and Langford, Paul R and Kroll, J Simon and Levin, Michael},
biburl = {https://www.bibsonomy.org/bibtex/20aa150d55fad50ac09666e2267ce16ad/jelias},
doi = {10.1080/00365540600643203},
interhash = {533926269758868e0132a66abf420639},
intrahash = {0aa150d55fad50ac09666e2267ce16ad},
issn = {0036-5548},
journal = {Scandinavian Journal of Infectious Diseases},
keywords = {Activity, Adolescent, Adult, Aged, Alleles, Ancestry B, Bactericidal Binding, Blood Britain, Child, Cohort Complement Continental Disease Disease, European Factor Family Genetic Great Group, H, Health, Homozygote, Humans, Infant, Infections, Meningococcal Middle Nucleotide, Polymorphism, Predisposition Preschool, Protein Single Statistics Studies, Susceptibility, Topic as to {Case-Control} {NF-kappa}},
note = {{PMID:} 16938729},
number = 9,
pages = {764--71},
timestamp = {2011-03-11T10:06:26.000+0100},
title = {Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in {UK} Caucasian patients},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16938729},
volume = 38,
year = 2006
}