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 (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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom. sa3@sanger.ac.uk
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Fry
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Diakite
authors.forename: Angela
authors.initials: A
authors.lastname: Green
authors.forename: Anna
authors.initials: A
authors.lastname: Richardson
authors.forename: Muminatou
authors.initials: M
authors.lastname: Jallow
authors.forename: Fatou
authors.initials: F
authors.lastname: Sisay-Joof
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Kasturi
authors.initials: K
authors.lastname: Haldar
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D005714:Gambia / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D008288:Malaria / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008295:Malawi / Q000453:epidemiology; D020710:RGS Proteins / Q000235:genetics; D018047:Receptors, Purinergic P1 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C454420:G-protein beta3 subunit; D020710:RGS Proteins; C087182:RGS2 protein, human; D018047:Receptors, Purinergic P1; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9
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