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A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children

Genes & Immunity volume 17, pages 52–59 (2016)Cite this article

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Abstract

Genetic factors are likely to contribute to low severe malaria case fatality rates in Melanesian populations, but association studies can be underpowered and may not provide plausible mechanistic explanations if significant associations are detected. In preparation for a genome-wide association study, 29 candidate single-nucleotide polymorphisms (SNPs) with minor allele frequencies >5% were examined in a case–control study of 504 Papua New Guinean children with severe malaria. In parallel, an immunological substudy was performed on convalescent peripheral blood mononuclear cells (PBMCs) from cases and controls. Following stimulation with a Toll-like receptor (TLR) 1/2 agonist, effector cytokines and chemokines were assayed. The only significant genetic association observed involved a nonsynonymous SNP (TLR1rs4833095) in the TLR1 gene. A recessive (TT) genotype was associated with reduced odds of severe malaria of 0.52 (95% confidence interval (0.29–0.90), P=0.006). Concentrations of pro-inflammatory cytokines interleukin-1β and tumour necrosis factor α were significantly higher in severe malaria cases compared with healthy controls, but lower in children with the protective recessive (TT) genotype. A genetic variant in TLR1 may contribute to the low severe malaria case fatality rates in this region through a reduced pro-inflammatory cellular phenotype.

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Acknowledgements

We gratefully acknowledge the assistance of staff on the Paediatric Ward at Modilon Hospital, the Papua New Guinea Institute of Medical Research staff at Modilon Hospital and the Yagaum campus, and the patients and their families for their participation. MalariaGEN is supported by the Wellcome Trust (WT077383/Z/05/Z) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (090770/Z/09/Z). Support was also provided by the Medical Research Council (G0600718). The Wellcome Trust also provides core awards to the Wellcome Trust Centre for Human Genetics (090532/Z/09/Z) and to the Wellcome Trust Sanger Institute (098051). Financial support for this study was also obtained from the National Health and Medical Research Council (NHMRC) of Australia (project grants 513782 and 516735 and program grant 637406). LS was supported by an International Research Scholarship of the Howard Hughes Medical Institute. LM was supported by Royal Australasian College of Physicians (Basser) and NHMRC scholarships, ML a Fogarty Foundation scholarship and TMED an NHMRC Practitioner Fellowship.

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Author notes

  1. J Cutts and D I Stanisic: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute, Fiona Stanley Hospital, Bull Creek, Western Australia, Australia

    L Manning & M Laman

  2. Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia

    J Cutts, D I Stanisic, A Carmagnac, H Karunajeewa, P Michon, L Schofield & I Mueller

  3. Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia

    J Cutts

  4. Institute for Glycomics, Griffith University, Southport, Queensland, Australia

    D I Stanisic

  5. Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea

    M Laman, A Rosanas-Urgell, P Siba & I Mueller

  6. Liverpool School of Tropical Medicine, Liverpool, UK

    S Allen

  7. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    A O’Donnell

  8. Institute of Tropical Medicine, Antwerp, Belgium

    A Rosanas-Urgell

  9. School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia

    T M E Davis

  10. Faculty of Health Sciences, Divine Word University, Madang, Papua New Guinea

    P Michon

  11. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    K Rockett & D Kwiatkowski

  12. Barcelona Center for International Health Research (CRESIB), Barcelona, Spain

    I Mueller

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Manning, L., Cutts, J., Stanisic, D. et al. A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children. Genes Immun 17, 52–59 (2016). https://doi.org/10.1038/gene.2015.50

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