Susceptibility to invasive meningococcal disease: polymorphism of complement system genes and Neisseria meningitidis factor H binding protein.

Declan T Bradley,Raymond Borrow,Derek J Fairley,Anne E Hughes,Thomas W Bourke,Michael D Shields,Peter F Zipfel

doi:10.1371/journal.pone.0120757

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.MethodsWe 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.ResultsRs12085435 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).DiscussionThe 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.

Highlights

The complement system is a fundamental part of the innate immune response
A complement factor H (CFH) haplotype tagged by rs3753396 G was associated with invasive meningococcal disease (IMD)
CFH haplotype did not affect the likelihood of infecting meningococci having either factor H binding protein (fHBP) subfamily

Summary

Introduction

The complement system is a fundamental part of the innate immune response This pathway harms unprotected surfaces by a powerful positive feedback cycle that injures cells by perforating them with circular polymers (the membrane attack complex) and by activating further immune response by releasing opsonins and anaphylatoxins [1,2,3]. Polymorphism of CFH and the adjacent homologous CFHR1–5 genes is associated with susceptibility to several inflammatory diseases [5,6,7,8,9,10]. 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

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Conclusion