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


Auburn, S; Fry, AE; Clark, TG; Campino, S; Diakite, M; Green, A; Richardson, A; Jallow, M; Sisay-Joof, F; Pinder, M; Molyneux, ME; Taylor, TE; Haldar, K; Rockett, KA; Kwiatkowski, DP; (2010) Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis. PLoS One, 5 (4). e10017. ISSN 1932-6203 DOI: https://doi.org/10.1371/journal.pone.0010017

[img]
Preview
Text - Published Version
License:

Download (136kB) | Preview

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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Faculty of Infectious and Tropical Diseases > Dept of Disease Control
Research Centre: Malaria Centre
PubMed ID: 20386734
Web of Science ID: 276418200065
URI: http://researchonline.lshtm.ac.uk/id/eprint/3640

Statistics


Download activity - last 12 months
Downloads since deposit
281Downloads
311Hits
Accesses by country - last 12 months
Accesses by referrer - last 12 months
Impact and interest
Additional statistics for this record are available via IRStats2

Actions (login required)

Edit Item Edit Item