Abstract

Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, Pmeta = 4.41 × 10−11, per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23–1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, Pmeta = 3.08 × 10−10, per-allele OR = 0.80 (95% confidence interval: 0.75–0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.

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Acknowledgements

This work was supported by the Wellcome Trust, United Kingdom (grant 088791/A/09/Z and 084368/Z/07/Z), and the Agency for Science, Technology and Research, Singapore.

Author information

Author notes

    • Martin L Hibberd
    •  & Cameron P Simmons

    These authors contributed equally to this work.

Affiliations

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

    • Chiea Chuen Khor
    • , Junxiong Pang
    • , Hoang Truong Long
    •  & Martin L Hibberd
  2. Genome Institute of Singapore–National University of Singapore Centre for Molecular Epidemiology, National University of Singapore, Singapore.

    • Chiea Chuen Khor
    • , Sonia Davila
    •  & Rick T H Ong
  3. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Chiea Chuen Khor
  4. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

    • Tran Nguyen Bich Chau
    • , Hoang Truong Long
    • , Sarah J Dunstan
    • , Bridget Wills
    • , Jeremy Farrar
    • , Nguyen Minh Nguyet
    •  & Cameron P Simmons
  5. Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Junxiong Pang
    • , Yik-Ying Teo
    •  & Martin L Hibberd
  6. Human Genetics, Genome Institute of Singapore, Singapore.

    • Sonia Davila
    • , Dennis E K Tan
    •  & Yik-Ying Teo
  7. Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.

    • Sarah J Dunstan
    • , Bridget Wills
    • , Jeremy Farrar
    •  & Cameron P Simmons
  8. Tien Giang Hospital, My Tho City, Tien Giang Province, Vietnam.

    • Ta Van Tram
    •  & Tran Thi Gan
  9. Sa Dec Hospital, Sa Dec Town, Dong Thap Province, Vietnam.

    • Nguyen Thi Nguyet Binh
    •  & Le Trung Tri
  10. Department of Dengue Hemorrhagic Fever, Children's Hospital No. 1, Ho Chi Minh City, Vietnam.

    • Le Bich Lien
    •  & Nguyen Minh Tuan
  11. Dong Thap Hospital, Cao Lanh City, Dong Thap Province, Vietnam.

    • Nguyen Thi Hong Tham
    •  & Mai Ngoc Lanh
  12. Hung Vuong Hospital, District 5, Ho Chi Minh City, Vietnam.

    • Nguyen Trong Hieu
  13. Hospital for Tropical Diseases, District 5, Ho Chi Minh City, Vietnam.

    • Nguyen Van N Vinh Chau
  14. Department of Infectious Diseases, Children's Hospital No. 2, District 1, Ho Chi Minh City, Vietnam.

    • Tran Thi Thuy
  15. Institut Pasteur, Laboratoire de la Génétique de la réponse aux infections chez l'homme, Paris, France.

    • Anavaj Sakuntabhai
  16. Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

    • Anavaj Sakuntabhai
  17. Department of Statistics and Applied Probability, Faculty of Science, National University of Singapore, Singapore.

    • Yik-Ying Teo

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Contributions

M.L.H. and C.P.S. are the study principal investigators who conceived and obtained funding for the project. C.C.K. organized and supervised the GWAS and replication genotyping pipeline, devised the overall analysis plan and wrote the first draft of the manuscript with input from M.L.H., C.P.S. and S.D. T.N.B.C. is the lead coordinator of clinical samples and phenotypes for both the discovery and replication stages. J.P. and D.E.K.T. performed genotyping and quality checks on all samples. C.C.K., S.D., R.T.H.O. and Y.-Y.T. analyzed the data. H.T.L., S.J.D., B.W., J.F., T.V.T., T.T.G., N.T.N.B., L.T.T., L.B.L., N.M.T., N.T.H.T., M.N.L., N.M.N., N.T.H., N.V.V.C., T.T.T. and A.S. coordinated and contributed patient and database phenotype collections as lead investigators for their respective sample collections. D.E.K.T. and J.P. performed genotyping and DNA quality checks. All authors critically reviewed manuscript revisions and contributed intellectual input to the final submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Martin L Hibberd or Cameron P Simmons.

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DOI

https://doi.org/10.1038/ng.960

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