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  • Original Article
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Haplotypic diversity in human CEACAM genes: effects on susceptibility to meningococcal disease

Genes & Immunity volume 9, pages 30–37 (2008)Cite this article

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.

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Acknowledgements

This study was funded by the Meningitis Research Foundation (project 02/02). DPK and KR are funded by the Medical Research Council. We wish to thank the staff at the core genomics and genotyping group at the Wellcome Trust Centre for Human Genetics, University of Oxford for their aid in Sequenom genotyping. AJP and MCJM are named as inventors, and MJC as a contributor, on a patent for the use of Opa proteins in meningococcal vaccines. All other authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Paediatrics, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Headington, Oxford, Oxon, UK,

    M J Callaghan & A J Pollard

  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    K Rockett, C Banner & D P Kwiatkowski

  3. Department of Clinical Molecular Genetics, Institute of Child Health, London, UK

    E Haralambous

  4. Department of Paediatrics, Faculty of Medicine, Wright Fleming Institute, Imperial College London, London, UK

    H Betts, J S Kroll & M Levin

  5. Wellcome Trust Clinical Research Facility, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK

    S Faust

  6. Department of Zoology, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK

    M C J Maiden

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  1. M J Callaghan
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  2. K Rockett
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  3. C Banner
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  4. E Haralambous
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Correspondence to M J Callaghan.

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Callaghan, M., Rockett, K., Banner, C. et al. Haplotypic diversity in human CEACAM genes: effects on susceptibility to meningococcal disease. Genes Immun 9, 30–37 (2008). https://doi.org/10.1038/sj.gene.6364442

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  • DOI: https://doi.org/10.1038/sj.gene.6364442

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