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Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease

Nature Genetics volume 42, pages 772776 (2010) | Download Citation


Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown1,2,3. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D<E), P = 2.2 × 10−11) and in CFH-related protein 3 (CFHR3)(rs426736, P = 4.6 × 10−13). N. meningitidis is known to evade complement-mediated killing by the binding of host CFH to the meningococcal factor H–binding protein (fHbp)4. Our study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen.

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We thank C.H. Wong, D. Tan, J.W. Tay, W.Y. Meah, S. Rajaram and C.B. Ang (Genome Institute of Singapore) for technical and logistical assistance. We also would like to thank all the children and parents who participated in this study. This study makes use of data generated by the Wellcome Trust Case-Control Consortium 2. A full list of the investigators who contributed to the generation of the data is available from the WTCCC website (see URLs). Funding for the project was provided by the Wellcome Trust under award 085475 (UK). The present work has been supported in part by funding from the Agency for Science and Technology and Research of Singapore (A*STAR) (Singapore). The UK meningococcal disease cohort was established with grant support from the Meningitis Research Foundation (UK). The coordination of the European cohorts was supported by a grant from the European Society for Pediatric Infectious Diseases. The Western Europe study was supported by grants no 8842, 10112 and 12710 of the Oesterreichische Nationalbank (Austria), grants A3-16.K-8/2008-11 and A3-16.K-8/2006-9 of the Department for Science and Research of the Styrian federal government (Austria) and the nonprofit association 'In Vita', Graz (Austria). The ESIGEM research group activities were supported by grants from Xunta de Galicia (PGIDIT06PXIB208079PR and Grupos Emerxentes: 2008/037), Fundación de Investigación Médica Mutua Madrileña (2008/CL444) and Ministerio de Ciencia e Innovación (SAF2008-02971) given to A.S.; Consellería de Sanidade (Xunta de Galicia, RHI07/2-intensificación actividad investigadora), Instituto Carlos III (Intensificación de la actividad investigadora), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007-2010), Fondo de Investigación Sanitaria (FIS; PI070069) del plan nacional de I+D+I and 'fondos FEDER' given to F.M.-T. M.E. was financially supported by the Erasmus MC Revolving Fund Foundation (RF 2001/24) (The Netherlands).

Author information

Author notes

    • Sonia Davila
    • , Victoria J Wright
    • , Michael Levin
    •  & Martin L Hibberd

    These authors contributed equally to this work.


  1. Infectious Diseases, Genome Institute of Singapore, Singapore.

    • Sonia Davila
    • , Chiea Chuen Khor
    • , Chui Chin Lim
    •  & Martin L Hibberd
  2. Division of Infectious Diseases, Department of Medicine, Imperial College London, UK.

    • Victoria J Wright
    • , David Inwald
    • , Simon Nadel
    • , Helen Betts
    •  & Michael Levin
  3. Research Computing, Genome Institute of Singapore, Singapore.

    • Kar Seng Sim
  4. Department of General Pediatrics, Medical University of Graz, Graz, Austria.

    • Alexander Binder
    •  & Werner Zenz
  5. Division of Pediatric Hematology, Immunology and Infectious diseases, Emma Children's Hospital Academic Medical Center, Amsterdam, The Netherlands.

    • Willemijn B Breunis
    •  & Taco W Kuijpers
  6. Institute of Child Health, University of Liverpool, Alder Hey Children's National Health Service Foundation Trust, Liverpool, UK.

    • Enitan D Carrol
  7. Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Ronald de Groot
    •  & Peter W M Hermans
  8. Department of Pediatrics, Erasmus Medical Center—Sophia Children's Hospital, University Medical Center, Rotterdam, The Netherlands.

    • Jan Hazelzet
    •  & Marieke Emonts
  9. Department of Immunology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.

    • Marieke Emonts
  10. Pediatric Emergency and Critical Care Division, Department of Pediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.

    • Federico Martinon-Torres
  11. Grupo Gallego de Genética, Vacunas e Investigación Pediátrica, Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.

    • Federico Martinon-Torres
  12. Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Galicia, Spain.

    • Antonio Salas
  13. Instituto de Medicina Legal, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Galicia, Spain.

    • Antonio Salas


  1. the International Meningococcal Genetics Consortium

    A full list of members is provided in the Supplementary Note.



    M.L. and M.L.H. conceived the study. S.D., V.J.W., M.L. and M.L.H. designed the study. V.J.W. and C.C.L. performed the experiments. S.D., V.J.W., C.C.K. and K.S.S. analyzed the data. A.B., W.B.B., D.I., S.N., H.B., E.D.C., R.d.G., P.W.M.H., J.H., M.E., T.W.K., F.M.T., A.S. and W.Z. coordinated national subject cohorts with collaborating clinicians (listed in the Supplementary Note) including sample collection and clinical data collection. S.D., V.J.W., C.C.K., M.L. and M.L.H. wrote the first draft of the manuscript. All authors contributed to the final version of the manuscript.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Sonia Davila or Michael Levin or Martin L Hibberd.

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      Supplementary Figures 1–6, Supplementary Tables 1–6 and Supplementary Note

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