Background
Invasive meningococcal disease (IMD) remains a severe bacterial infection with high death and disability rates worldwide. Although several risk factors for IMD have been identified, the biological basis of inter-individual susceptibility and the reasons for vaccine failure in some individuals remain incompletely understood. Single nucleotide polymorphisms (SNPs) are thought to contribute to inter-individual differences in disease susceptibility. In recent years several studies have investigated the relationship between SNPs in genes that regulate inflammation, immunity, coagulation and fibrinolysis and susceptibility to IMD, many with apparently conflicting results. We conducted a systematic review and meta-analysis to identify host genetic polymorphisms that confer susceptibility to IMD.
Methods
A systematic search of Embase, MEDLINE, and Google Scholar identified studies examining host genetic variants associated with susceptibility to IMD. The protocol was prospectively registered on PROSPERO (CRD420251162856). Data were pooled using a DerSimonian and Laird random-effects model. Effect estimates were summarised as odds ratios (ORs) with 95% confidence intervals (CIs), and heterogeneity was assessed using I² statistics.
Results
A total of 6,879 studies were screened and 81 studies provided data on host genetic polymorphisms and IMD. The polymorphism rs1065489 in the complement factor H (CFH) gene showed a significant protective association, with pooled analysis indicating reduced odds of IMD among carriers of the minor allele (OR 0.59, 95% CI 0.43 - 0.81). The pooled estimate of the minor allele frequency was 21.9% among IMD cases and 32.5% among controls. The other evaluated polymorphisms showed non-significant associations.
Conclusions
CFH encodes factor H, a key regulator of the alternative complement pathway, which protects host tissues from excessive complement activation. Neisseria meningitidis expresses factor H binding protein (fHbp) on its surface, which helps to evade complement-mediated killing in the bloodstream. Individuals carrying the protective T allele of rs1065489 are considered to have a more effective innate immune response against meningococci. However, rs1065489 is in linkage disequilibrium with variants in neighbouring CFH-related genes and the observed association may reflect a broader protective haplotype.