title: Susceptibility to invasive meningococcal disease: polymorphism of complement system genes and Neisseria meningitidis factor H binding protein.
abstract: BACKGROUND
  Neisseria 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Rs12085435 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).
  
  
  CONCLUSIONS
  The 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.
authors: Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom; Public Health Agency, Belfast, United Kingdom.
authors: Declan T
authors: DT
authors: Bradley
authors: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.
authors: Thomas W
authors: TW
authors: Bourke
authors: Regional Virus Laboratory, Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors: Derek J
authors: DJ
authors: Fairley
authors: Vaccine Evaluation Unit, Public Health England, Manchester, United Kingdom; Inflammation Sciences Research Group, School of Translational Medicine, University of Manchester, Manchester, United Kingdom.
authors: Raymond
authors: R
authors: Borrow
authors: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.
authors: Michael D
authors: MD
authors: Shields
authors: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany; Friedrich Schiller University, Jena, Germany.
authors: Peter F
authors: PF
authors: Zipfel
authors: Formerly of Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.
authors: Anne E
authors: AE
authors: Hughes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D017242:Complement Factor H / Q000235:genetics; D003171:Complement Pathway, Classical; D003165:Complement System Proteins / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D051916:Membrane Cofactor Protein / Q000235:genetics; D008589:Meningococcal Infections / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D009345:Neisseria meningitidis / Q000502:physiology*; D011110:Polymorphism, Genetic; D012008:Recurrence; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D051916:Membrane Cofactor Protein; C484699:factor H-binding protein, Neisseria meningitidis; D017242:Complement Factor H; D003165:Complement System Proteins