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Association of the GNAS locus with severe malaria

Auburn, S., Diakite, M., Fry, A. E., Ghansah, A., Campino, S., Richardson, A., Jallow, M., Sisay-Joof, F., Pinder, M., Griffiths, M. J., Peshu, N., Williams, T. N., Marsh, Kevin, Molyneux, Malcolm E, Taylor, T. E., Koram, K. A., Oduro, A. R., Rogers, W. O., Rockett, K. A., Haldar, K. and Kwiatkowski, D. P. (2008) 'Association of the GNAS locus with severe malaria'. Human Genetics, Vol 124, Issue 5, pp. 499-506.

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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.

Item Type: Article
Uncontrolled Keywords: plasmodium-falciparum infection proteins amplification cholesterol linkage gene cell
Subjects: WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 150 Erythrocytes
Faculty: Department: Groups (2002 - 2012) > Clinical Group
Digital Object Identifer (DOI): https://doi.org/10.1007/s00439-008-0575-8
Depositing User: Users 43 not found.
Date Deposited: 25 Aug 2010 09:33
Last Modified: 06 Feb 2018 13:00
URI: http://archive.lstmed.ac.uk/id/eprint/725

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