TY - JOUR
T1 - Association of the GNAS locus with severe malaria
AU - Auburn, Sarah
AU - Diakite, Mahamadou
AU - Fry, Andrew E.
AU - Ghansah, Anita
AU - Campino, Susana
AU - Richardson, Anna
AU - Jallow, Muminatou
AU - Sisay-Joof, Fatou
AU - Pinder, Margaret
AU - Griffiths, Michael J.
AU - Peshu, Norbert
AU - Williams, Thomas N.
AU - Marsh, Kevin
AU - Molyneux, Malcolm E.
AU - Taylor, Terrie E.
AU - Koram, Kwadwo A.
AU - Oduro, Abraham R.
AU - Rogers, William O.
AU - Rockett, Kirk A.
AU - Haldar, Kasturi
AU - Kwiatkowski, Dominic P.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=57049102286&partnerID=8YFLogxK
U2 - 10.1007/s00439-008-0575-8
DO - 10.1007/s00439-008-0575-8
M3 - Article
C2 - 18951142
AN - SCOPUS:57049102286
SN - 0340-6717
VL - 124
SP - 499
EP - 506
JO - Human Genetics
JF - Human Genetics
IS - 5
ER -