Abstract
Functional studies have demonstrated an interaction between the stimulatory G protein alpha subunit (G-alpha-s) and the malaria parasite at a cellular level. Obstruction of signal transduction via the erythrocyte G-alpha-s subunit reduced invasion by Plasmodium falciparum parasites. We sought to determine whether this signal pathway had an impact at the disease level by testing polymorphisms in the gene encoding G-alpha-s (GNAS) for association with severe malaria in a large multi-centre study encompassing family and case–control studies from The Gambia, Kenya and Malawi, and a case–control study from Ghana. We gained power to detect association using meta-analysis across the seven studies, with an overall sample size approximating 4,000 cases and 4,000 controls. Out of 12 SNPs investigated in the 19 kb GNAS region, four presented signals of association (P < 0.05) with severe malaria. The strongest single-locus association demonstrated an odds ratio of 1.13 (1.05–1.21), P = 0.001. Three of the loci presenting significant associations were clustered at the 5-prime end of the GNAS gene. Accordingly, haplotypes constructed from these loci demonstrated significant associations with severe malaria [OR = 0.88 (0.81–0.96), P = 0.005 and OR = 1.12 (1.03–1.20), P = 0.005]. The evidence presented here indicates that the influence of G-alpha-s on erythrocyte invasion efficacy may, indeed, alter individual susceptibility to disease.
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Acknowledgments
We wish to thank Dr. Taane Clark, Dr. YY Teo and Dr. Andrew Morris for their statistical advice. SA was supported by a PhD studentship from the Medical Research council, UK. MD was supported by a training fellowship from the International Atomic Energy Agency. AEF and MJG were funded by Wellcome Trust Training Fellowships. SC was funded by a Marie-Curie Intra-European Fellowship (FP6). TNW and KM were funded by a Wellcome Trust grant. The genetic component of this research was funded by a Medical Research Council (UK) grant to Professor Dominic Kwiatkowski and a National Institute of Health (USA) grant to Professor Kasturi Haldar. This study is part of the European Union Network of Excellence on the biology of malaria parasites. This manuscript is published with the permission of the director of the Kenya Medical Research Institute.
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Auburn, S., Diakite, M., Fry, A.E. et al. Association of the GNAS locus with severe malaria. Hum Genet 124, 499–506 (2008). https://doi.org/10.1007/s00439-008-0575-8
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DOI: https://doi.org/10.1007/s00439-008-0575-8