Genetic factors determining susceptibility and severity of meningococcal disease
Dr Martin Hibberd, Professor Michael Levin
- Start Date:
01 January 2000
Imperial College School of Medicine at St Mary's Hospital, London, UK
Although the vast majority of people are colonised by Neissera meningitidis at some point during their lives, less than 0.01% are affected by meningococcal disease (MD) and most of these suffer a relatively mild form of the disease, suggesting that host factors play a role in both susceptibility and severity. Over the last 3 years, work at Imperial College funded by the Meningitis Research Foundation has made a major contribution to our understanding of these host factors. Not only has an extensive collection of samples been established, but our studies (two of which have been published in the Lancet) have established a role for variation in the host response in determining disease progression. We will now undertake a continued program of work to maximise the information which can be obtained from the patient information and samples. In collaboration with other leading centres, we will investigate new candidates for association with susceptibility or severity of MD in the cytokine genes, innate immunity genes and the MHC locus, in three separate populations. We will, where possible, correlate genetic variation with gene product (protein) variation in patient plasma, and we will assess interactions between positively associated genes. Particular genes may be found which are highly predictive of disease risk (or dying) and the pathways these genes control will then become targets for novel therapies.
Results from this study have been published in scientific journals as follows:
Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, Beutler B.
Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility.
Proc Natl Acad Sci U S A 2003 May 13;100(10):6075-80. Epub 2003 May 2.
Haralambous E, Weiss HA, Radalowicz A, Hibberd ML, Booy R, Levin M.
Sibling familial risk ratio of meningococcal disease in UK Caucasians.
Epidemiol Infect 2003 Jun;130(3):413-8.
Haralambous E, Hibberd ML, Hermans PW, Ninis N, Nadel S, Levin M.
Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children.
Crit Care Med 2003 Dec;31(12):2788-93.