Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491304
Title: Host Genetic Components of the Erythrocyte Stimulatory G Protein Signal Pathway that Determine Susceptibility to Severe Malaria
Author: Auburn, Sarah
ISNI:       0000 0001 3432 7464
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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Abstract:
The host stimulatory G protein signal transduction pathway has been functionally implicated in the modulation of erythrocyte invasion by Pjalciparum, and putatively implicated in the establishment of new permeability pathways in Pjalciparum-infected erythrocytes. The objective of this thesis was to identify whether the G protein pathway has genetic determinants involved in severe malaria pathogenesis. I investigated eleven components of the G protein pathway; GNAS, f3-2-AR, ADORA2A, ADORA2B, ADRBKJ, RGS2, GNB3, ADCY9, CFTR and P2RYJ. GNAS SNPs were genotyped in 7 studies (family and population-based) while f3-2-AR and all other genes were genotyped in either a single population-based study or a single family-based study, respectively. The most compelling association was observed at the GNAS locus, encoding G-alpha-s. Meta-analysis across 7 studies revealed significant association between an intronic variant, rs2057291, and severe malaria (P=O.002). I used allele-specific transcript quantification mapping in the attempt to map putative cis-regulatory polymorphisms in G-alpha-s transcription that might explain the rs2057291 association. Using B cells from fifteen HapMap individuals, I found evidence of relative allelic transcription imbalance in two cell lines (ratio C to T allele -1.3). However, mapping analysis was limited by sample size and failed to identify a plausible candidate for this regulatory effect. Analysis of P-2-AR and P-I-AR was limited due to difficulties in genotyping several key SNPs and, therefore, the role of these genes in severe malaria remains unclear. However, genotyping in the other genes revealed a promising association with a non-synonymous SNP in the catalytic domain of the ADCY9 gene, rs2230739 (ile772met), which had previously been shown to be functional in the regulation of cAMP production and [3-2-AR stimulation (P=O.027). This association requires validation in further studies. In conclusion, the involvement of the G protein pathway in severe malaria deserves further investigation. Future studies should focus on characterizing and replicating significant associations identified here and elucidating other important components of the pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: University of Oxford, 2007 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.491304  DOI: Not available
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