Journal Article

Common variation in the ABO glycosyltransferase is associated with susceptibility to severe <i>Plasmodium falciparum</i> malaria

Andrew E. Fry, Michael J. Griffiths, Sarah Auburn, Mahamadou Diakite, Julian T. Forton, Angela Green, Anna Richardson, Jonathan Wilson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Norbert Peshu, Thomas N. Williams, Kevin Marsh, Malcolm E. Molyneux, Terrie E. Taylor, Kirk A. Rockett and Dominic P. Kwiatkowski

in Human Molecular Genetics

Volume 17, issue 4, pages 567-576
Published in print February 2008 | ISSN: 0964-6906
Published online November 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm331
Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria

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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 × 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.

Journal Article.  7098 words.  Illustrated.

Subjects: Genetics and Genomics

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