title: A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children.
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.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute, Fiona Stanley Hospital, Bull Creek, Western Australia, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Manning
authors.affiliation: Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia.|Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Cutts
authors.affiliation: Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia.|Institute for Glycomics, Griffith University, Southport, Queensland, Australia.
authors.forename: D I
authors.initials: DI
authors.lastname: Stanisic
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute, Fiona Stanley Hospital, Bull Creek, Western Australia, Australia.|Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: M
authors.initials: M
authors.lastname: Laman
authors.affiliation: Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Carmagnac
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: S
authors.initials: S
authors.lastname: Allen
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: O'Donnell
authors.affiliation: Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Karunajeewa
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.|Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Rosanas-Urgell
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: P
authors.initials: P
authors.lastname: Siba
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: T M E
authors.initials: TM
authors.lastname: Davis
authors.affiliation: Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia.|Faculty of Health Sciences, Divine Word University, Madang, Papua New Guinea.
authors.forename: P
authors.initials: P
authors.lastname: Michon
authors.affiliation: Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Schofield
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Rockett
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: D
authors.initials: D
authors.lastname: Kwiatkowski
authors.affiliation: Infection and Immunity Division, Walter & Eliza Hall Institute, Parkville, Melbourne, Australia.|Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.|Barcelona Center for International Health Research (CRESIB), Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Mueller
mesh_terms: D016022:Case-Control Studies; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016778:Malaria, Falciparum / Q000235:genetics* / Q000276:immunology* / Q000469:parasitology; D008297:Male; D010219:Papua New Guinea; D020641:Polymorphism, Single Nucleotide; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000276:immunology*
chemical_list: D051194:Toll-Like Receptor 1