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Summary Background The reasons why meningococcal disease develops in only a small proportion of individuals carrying the causative bacteria are unknown. Differences in host responses to bacterial colonisation are thought to be involved, since people with deficiencies in the terminal components of the complement pathway, or of properdin, are susceptible to meningococcal disease. We postulate that genetic variants of mannose-binding lectin (MBL), a plasma opsonin that initiates another pathway of complement activation, might similarly cause susceptibility to meningococcal disease. Methods The frequency of variants of the MBL gene was ascertained in children with meningococcal disease and controls from two independent studies; one hospital-based (194 patients and 272 controls [patients with noninfectious disorders]), and one community-based (72 patients and 110 controls [healthy individuals]), by means of PCR and restriction-enzyme digestion, with confirmation by DNA sequencing. Findings The proportion of people homozygous for MBL -variant alleles was higher in patients with meningococcal disease than in controls in the hospital study (15 [7·7%] vs four [1·5%]; odds ratio 6·5 [95% CI 2·0–27·2]) and in the community study (six [8·3%] vs three [2·7%]; 4·5 [0·9–29·1]). The population attributable fraction of cases attributable to MBL variants (homozygous and heterozygous) was 32%. Interpretation The MBL pathway is a critical determinant of meningococcal-disease susceptibility, and genetic variants of MBL might account for a third of all disease cases.

Summary Background Persistent infection with hepatitis B virus (HBV) affects 350 million people worldwide, and 20–40% of infected patients die of cirrhosis and liver cancer. Little is known about the host factors that determine the variable natural history. Studies have focused on the role of acquired rather than innate immunity. We have investigated the prevalence of mutations in the gene for mannose-binding protein (MBP), which have been associated with susceptibility to bacterial and fungal infections. Methods Mutations in the MBP gene were sought by sequence-specific oligonucleotide hybridisation, site-directed mutagenesis polymerase chain amplification, and direct sequencing in Caucasian and Asian patients with HBV infection, and in HBsAg-negative controls. Findings A mutation in codon 52 of the MBP gene was present in two (11%) of 19 Caucasian patients with acute hepatitis B and nine (27%) of 33 Caucasian patients with chronic hepatitis B, compared with four (4%) of 98 Caucasian controls (p=0·0004). By contrast, the prevalence of the mutation was similar in Asian patients with chronic hepatitis B and in Asian controls (one [5%] of 20 vs two [2%] of 117). Mutations in codon 54 and codon 57 were found in similar proportions of patients and controls. Interpretation These findings show in Caucasian, but not Asian, patients an association of the codon 52 mutation of the MBP gene with persistent HBV infection. They suggest an important role for this gene, or a gene in linkage disequilibrium with MBP , in determining outcome after HBV infection in adult but not neonatal life.

Low serum mannose-binding protein (MBP) concentrations are associated with a common opsonic defect. Sequence analysis of the MBP gene in three children with recurrent infections, the opsonic defect, and low serum MBP concentrations showed a point mutation at base 230 of exon 1 causing a change of codon 54 from GGC to GAC. The replacement of glycine with an aspartic acid residue disrupts the fifth Gly-Xaa-Yaa repeat in the collagen-like domain of each 32 kD MBP peptide chain and probably prevents the formation of the normal triple helix. Study of sixteen members of the three families showed autosomal dominant coinheritance of the mutation and low serum MBP concentrations.