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

Manning, L, Cutts, J, Stanisic, D I, Laman, M, Carmagnac, A, Allen, Stephen ORCID: https://orcid.org/0000-0001-6675-249X, O'Donnell, A, Karunajeewa, H, Rosanas-Urgell, A, Siba, P, Davis, T M E, Michon, P, Schofield, L, Rockett, K, Kwiatkowski, D and Mueller, I (2015) 'A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children'. Genes and Immunity, Vol 17, pp. 52-59.

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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.

Item Type:	Article
Corporate Authors:	MalariaGEN Consortium
Subjects:	QU Biochemistry > Genetics > QU 500 Genetic phenomena WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WS Pediatrics > WS 100 General works
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1038/gene.2015.50
Depositing User:	Jessica Jones
Date Deposited:	26 Jan 2016 13:16
Last Modified:	12 Sep 2019 13:28
URI:	https://archive.lstmed.ac.uk/id/eprint/5531

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