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Reference: Auburn, S, Fry, AE, Clark, TG et al., (2010). Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis. PLoS One, 5 (4), e10017-e10017.Citable link to this page:


Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis

Abstract: With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's version Funder: Medical Research Council   Funder: National Institutes of Health (USA)   Funder: Wellcome Trust   Funder: Bill and Melinda Gates Foundation   Funder: Marie-Curie intra-European fellowship   Funder: International Atomic Energy Agency   Notes:file: :C$$:/Users/dominic/Dropbox/Refs/2010/Auburn et al._2010_Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis.pdf:pdfkeywords: dkcvmendeley-tags: dkcvNotes:This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose

Bibliographic Details

Publisher: Public Library of Science

Publisher Website: http://www.plos.org


Publisher Website: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieveanddb=PubMedanddopt=Citationandlist_uids=20386734

Journal: PLoS Onesee more from them

Publication Website: http://www.plosone.org

Issue Date: 2010

pages:Article: e10017


Urn: uuid:f941bbf6-44d3-4749-9863-3c3f8102c337

Source identifier: 53295

Eissn: 1932-6203

Doi: https://doi.org/10.1371/journal.pone.0010017

Issn: 1932-6203 Item Description

Type: Journal article;

Language: eng

Version: Publisher's versionKeywords: Humans Malaria Adenylate Cyclase RGS Proteins Heterotrimeric GTP-Binding Proteins GTP-Binding Protein alpha Subunits, Gs Receptors, Purinergic P1 Case-Control Studies Signal Transduction Family Health Child Child, Preschool Infant G-Protein-Coupled Receptor Kinase 2 Genetic Predisposition to Disease Malawi Gambia Tiny URL: pubs:53295


Author: Auburn, S - institutionUniversity of Oxford - - - Fry, AE - institutionUniversity of Oxford fundingWellcome Trust - - - Clark, TG

Source: https://ora.ox.ac.uk/objects/uuid:f941bbf6-44d3-4749-9863-3c3f8102c337


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