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Human Molecular Genetics Advance Access originally published online on November 13, 2007
Human Molecular Genetics 2008 17(4):567-576; doi:10.1093/hmg/ddm331
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria

Andrew E. Fry1,*, Michael J. Griffiths1,2, Sarah Auburn1, Mahamadou Diakite1, Julian T. Forton1, Angela Green1, Anna Richardson1, Jonathan Wilson1, Muminatou Jallow3, Fatou Sisay-Joof3, Margaret Pinder3, Norbert Peshu2, Thomas N. Williams2,4, Kevin Marsh2,4, Malcolm E. Molyneux5,7, Terrie E. Taylor6,8, Kirk A. Rockett1 and Dominic P. Kwiatkowski1,9

1 The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK 2 Kenya Medical Research, Institute Centre for Geographical Medicine Research (Coast), PO Box 230, Kilifi, Kenya 3 Medical Research Council, PO Box 273, Banjul, The Gambia 4 Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK 5 The Malawi–Liverpool–Wellcome Trust Programme of Clinical Tropical Research 6 Blantyre Malaria Project, College of Medicine, PO Box 30096, Blantyre, Malawi 7 Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK 8 Department of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan 48824, USA 9 Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK

* To whom correspondence should be addressed at: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. Tel: +44 1865287536; fax: +44 1865287533; Email: afry{at}well.ox.ac.uk

Received October 9, 2007; Revised November 7, 2007; Accepted November 9, 2007

There is growing epidemiological and molecular evidence that ABO blood group affects host susceptibility to severe Plasmodium falciparum infection. The high frequency of common ABO alleles means that even modest differences in susceptibility could have a significant impact on the health of people living in malaria endemic regions. We performed an association study, the first to utilize key molecular genetic variation underlying the ABO system, genotyping >9000 individuals across three African populations. Using population- and family-based tests, we demonstrated that alleles producing functional ABO enzymes are associated with greater risk of severe malaria phenotypes (particularly malarial anemia) in comparison with the frameshift deletion underlying blood group O: case–control allelic odds ratio (OR), 1.2; 95% confidence interval (CI), 1.09–1.32; P = 0.0003; family-studies allelic OR, 1.19; 95% CI, 1.08–1.32; P = 0.001; pooled across all studies allelic OR, 1.18; 95% CI, 1.11–1.26; P = 2 x 10–7. We found suggestive evidence of a parent-of-origin effect at the ABO locus by analyzing the family trios. Non-O haplotypes inherited from mothers, but not fathers, are significantly associated with severe malaria (likelihood ratio test of Weinberg, P = 0.046). Finally, we used HapMap data to demonstrate a region of low FST (–0.001) between the three main HapMap population groups across the ABO locus, an outlier in the empirical distribution of FST across chromosome 9 (~99.5–99.9th centile). This low FST region may be a signal of long-standing balancing selection at the ABO locus, caused by multiple infectious pathogens including P. falciparum.


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