Letter | Published:

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

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

GenBank/EMBL/DDBJ

References

  1. 1.

    , , & Host genetic determinants of Neisseria meningitidis infections. Lancet Infect. Dis. 3, 565–577 (2003).

  2. 2.

    et al. Sibling familial risk ratio of meningococcal disease in UK Caucasians. Epidemiol. Infect. 130, 413–418 (2003).

  3. 3.

    , & Genetic polymorphisms in host response to meningococcal infection: the role of susceptibility and severity genes. Vaccine 27 Suppl 2, B90–B102 (2009).

  4. 4.

    et al. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature 458, 890–893 (2009).

  5. 5.

    , & Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin. Microbiol. Rev. 13, 144–166 (2000).

  6. 6.

    & Complement and properidin deficiencies in meningococcal disease. Pediatr. Infect. Dis. J. 25, 255–256 (2006).

  7. 7.

    et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 335, 1941–1949 (1996).

  8. 8.

    et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc. Natl. Acad. Sci. USA 100, 6075–6080 (2003).

  9. 9.

    , , , & Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group. Lancet 353, 1049–1053 (1999).

  10. 10.

    et al. Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients. Scand. J. Infect. Dis. 38, 764–771 (2006).

  11. 11.

    et al. 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. 31, 2788–2793 (2003).

  12. 12.

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  13. 13.

    et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  14. 14.

    , & Global epidemiology of meningococcal disease. Vaccine 27 Suppl 2, B51–B63 (2009).

  15. 15.

    , & A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

  16. 16.

    et al. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet. 3, e41 (2007).

  17. 17.

    et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat. Genet. 38, 1173–1177 (2006).

  18. 18.

    , , , & Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes. Mol. Immunol. 37, 41–52 (2000).

  19. 19.

    et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

  20. 20.

    , , , & Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome. Blood 114, 4261–4271 (2009).

  21. 21.

    et al. Host genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis. Lancet Infect. Dis. 9, 31–44 (2009).

  22. 22.

    Diagnosing meningococcemia as a cause of sepsis. Pediatr. Crit. Care Med. 6, S50–S54 (2005).

  23. 23.

    , , & Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. J. Infect. Dis. 174, 878–880 (1996).

  24. 24.

    et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia. Eur. J. Pediatr. 164, 486–490 (2005).

  25. 25.

    et al. Protein C promoter polymorphisms associate with sepsis in children with systemic meningococcemia. Hum. Genet. 122, 183–190 (2007).

  26. 26.

    et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 354, 556–560 (1999).

  27. 27.

    et al. A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet. 5, e1000319 (2009).

  28. 28.

    , , , & Investigating the role of mitochondrial haplogroups in genetic predisposition to meningococcal disease. PLoS ONE 4, e8347 (2009).

  29. 29.

    , , & Defensins and the dynamic genome: what we can learn from structural variation at human chromosome band 8p23.1. Genome Res. 18, 1686–1697 (2008).

  30. 30.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

Download references

Acknowledgements

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.

Affiliations

  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

Consortia

  1. the International Meningococcal Genetics Consortium

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

Authors

    Contributions

    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.

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

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

    About this article

    Publication history

    Received

    Accepted

    Published

    DOI

    https://doi.org/10.1038/ng.640

    Further reading