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

Fry, A. E., Griffiths, M. J., Auburn, S., Diakite, M., Forton, J. T., Green, A., Richardson, A., Wilson, J., Jallow, M., Sisay-Joof, F., Pinder, M., Peshu, N., Williams, T. N., Marsh, Kevin, Molyneux, Malcolm E, Taylor, T. E., Rockett, K. A. and Kwiatkowski, D. P. (2008) 'Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria'. Human Molecular Genetics, Vol 17, Issue 4, pp. 567-576.

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Abstract

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 F-ST (-0.001) between the three main HapMap population groups across the ABO locus, an outlier in the empirical distribution of F-ST across chromosome 9 (similar to 99.5-99.9th centile). This low F-ST region may be a signal of long-standing balancing selection at the ABO locus, caused by multiple infectious pathogens including P. falciparum.

Item Type: Article
Uncontrolled Keywords: blood-group antigens haplotype reconstruction natural-selection cerebral malaria human genome var genes group-a system cell resistance
Subjects: QU Biochemistry > Genetics > QU 470 Genetic structures
QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 755 Epidemiology
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 420 Blood groups. Blood group incompatibility (General)
Faculty: Department: Groups (2002 - 2012) > Clinical Group
Digital Object Identifer (DOI): https://doi.org/10.1093/hmg/ddm331
Depositing User: Users 43 not found.
Date Deposited: 19 Aug 2010 11:38
Last Modified: 06 Feb 2018 13:00
URI: https://archive.lstmed.ac.uk/id/eprint/782

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