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

Sarah Auburn, Andrew Fry, Taane Clark, Susana Campino, Mahamadou Diakite, Angela Green, Anna Richardson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Malcolm Molyneux, Terrie Taylor, Kasturi Haldar, Kirk Rockett, Dominic Kwiatkowski

Research output: Contribution to journalArticleResearchpeer-review

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 (∼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.
Original languageEnglish
Article numbere10017
Pages (from-to)1-7
Number of pages7
JournalPLoS One
Volume5
Issue number4
DOIs
Publication statusPublished - 1 Apr 2010
Externally publishedYes

Fingerprint

Signal transduction
malaria
Malaria
signal transduction
Signal Transduction
pathogenesis
Genes
Gs GTP-Binding Protein alpha Subunits
G-proteins
Association reactions
genes
G-Protein-Coupled Receptor Kinase 2
GTP-Binding Protein Regulators
Gambia
alleles
Malawi
adenylate cyclase
Purinergic P1 Receptors
antimalarials
Antimalarials

Cite this

Auburn, S., Fry, A., Clark, T., Campino, S., Diakite, M., Green, A., ... Kwiatkowski, D. (2010). Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis. PLoS One, 5(4), 1-7. [e10017]. https://doi.org/10.1371/journal.pone.0010017
Auburn, Sarah ; Fry, Andrew ; Clark, Taane ; Campino, Susana ; Diakite, Mahamadou ; Green, Angela ; Richardson, Anna ; Jallow, Muminatou ; Sisay-Joof, Fatou ; Pinder, Margaret ; Molyneux, Malcolm ; Taylor, Terrie ; Haldar, Kasturi ; Rockett, Kirk ; Kwiatkowski, Dominic. / Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis. In: PLoS One. 2010 ; Vol. 5, No. 4. pp. 1-7.
@article{07f47bbf93cc4829836adb4535f4d2fb,
title = "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 (∼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.",
author = "Sarah Auburn and Andrew Fry and Taane Clark and Susana Campino and Mahamadou Diakite and Angela Green and Anna Richardson and Muminatou Jallow and Fatou Sisay-Joof and Margaret Pinder and Malcolm Molyneux and Terrie Taylor and Kasturi Haldar and Kirk Rockett and Dominic Kwiatkowski",
year = "2010",
month = "4",
day = "1",
doi = "10.1371/journal.pone.0010017",
language = "English",
volume = "5",
pages = "1--7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science (PLoS)",
number = "4",

}

Auburn, S, Fry, A, Clark, T, Campino, S, Diakite, M, Green, A, Richardson, A, Jallow, M, Sisay-Joof, F, Pinder, M, Molyneux, M, Taylor, T, Haldar, K, Rockett, K & Kwiatkowski, D 2010, 'Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis', PLoS One, vol. 5, no. 4, e10017, pp. 1-7. https://doi.org/10.1371/journal.pone.0010017

Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis. / Auburn, Sarah; Fry, Andrew; Clark, Taane; Campino, Susana; Diakite, Mahamadou; Green, Angela; Richardson, Anna; Jallow, Muminatou; Sisay-Joof, Fatou; Pinder, Margaret; Molyneux, Malcolm; Taylor, Terrie; Haldar, Kasturi; Rockett, Kirk; Kwiatkowski, Dominic.

In: PLoS One, Vol. 5, No. 4, e10017, 01.04.2010, p. 1-7.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis

AU - Auburn, Sarah

AU - Fry, Andrew

AU - Clark, Taane

AU - Campino, Susana

AU - Diakite, Mahamadou

AU - Green, Angela

AU - Richardson, Anna

AU - Jallow, Muminatou

AU - Sisay-Joof, Fatou

AU - Pinder, Margaret

AU - Molyneux, Malcolm

AU - Taylor, Terrie

AU - Haldar, Kasturi

AU - Rockett, Kirk

AU - Kwiatkowski, Dominic

PY - 2010/4/1

Y1 - 2010/4/1

N2 - 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 (∼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.

AB - 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 (∼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.

UR - http://www.scopus.com/inward/record.url?scp=77956336730&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0010017

DO - 10.1371/journal.pone.0010017

M3 - Article

VL - 5

SP - 1

EP - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e10017

ER -