1. ¹Department of Paediatrics, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Headington, Oxford, Oxon, UK
2. ²Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
3. ³Department of Clinical Molecular Genetics, Institute of Child Health, London, UK
4. ⁴Department of Paediatrics, Faculty of Medicine, Wright Fleming Institute, Imperial College London, London, UK
5. ⁵Wellcome Trust Clinical Research Facility, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK
6. ⁶Department of Zoology, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK

Correspondence: Dr MJ Callaghan, Department of Paediatrics, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Headington, Oxford, Oxon OX3 7LJ, UK. E-mail: martin.callaghan@paediatrics.ox.ac.uk

Received 1 June 2007; Revised 24 September 2007; Accepted 24 September 2007; Published online 25 October 2007.

Abstract

Adhesion between the opacity-associated adhesin (Opa) proteins of Neisseria meningitidis and human carcino-embryonic antigen cell adhesion molecule (CEACAM) proteins is an important stage in the pathogenesis of meningococcal disease, a globally important bacterial infection. Most disease is caused by a small number of meningococcal genotypes known as hyperinvasive lineages. As these are also carried asymptomatically, acquisition of them alone cannot explain why only some hosts develop meningococcal disease. Our aim was to determine whether genetic diversity in CEACAM is associated with susceptibility to meningococcal disease. Frequency distributions of alleles, genotypes and haplotypes were compared in four CEACAM genes in 384 case samples and 190 controls. Linkage disequilibrium among polymorphic sites, haplotype structures and relationships were also analysed. A number of polymorphisms were observed in CEACAM genes but the diversity of CEACAM1, to which most Opa proteins bind, was lower, and a small number of high-frequency haplotypes were detected. Dose-dependent associations of three CEACAM haplotypes with meningococcal disease were observed, with the effect of carrying these haplotypes amplified in homozygous individuals. Two haplotypes were protective while one haplotype in CEACAM6 was associated with a twofold increase in disease susceptibility. These data imply that human CEACAM may be one determinant of human susceptibility to meningococcal disease.