Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease

Background The reasons why meningococcal disease develops in only a small p roportion of individuals carrying the causative bacteria are unknown. Diffe rences in host responses to bacterial colonisation are thought to be involv ed, since people with deficiencies in the terminal components of the comple ment 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 simi larly cause susceptibility to meningococcal disease. Methods The frequency of variants of the MBL gene was ascertained in childr en with meningococcal disease and controls from two independent studies; on e hospital-based (194 patients and 272 controls [patients with noninfectiou s disorders]), and one community-based (72 patients and 110 controls [healt hy individuals]), by means of PCR and restriction-enzyme digestion, with co nfirmation by DNA sequencing. Findings The proportion of people homozygous for MBL-variant alleles was hi gher in patients with meningococcal disease than in controls in the hospita l 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 popu lation attributable fraction of cases attributable to MBL variants (homozyg ous and heterozygous) was 32%, Interpretation The MBL pathway is a critical determinant of meningococcal-d isease susceptibility, and genetic variants of MBL might account for a thir d of all disease cases.