Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria.
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 (approximately 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.
Fry
Andrew E
AE
The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. afry@well.ox.ac.uk
Griffiths
Michael J
MJ
Auburn
Sarah
S
Diakite
Mahamadou
M
Forton
Julian T
JT
Green
Angela
A
Richardson
Anna
A
Wilson
Jonathan
J
Jallow
Muminatou
M
Sisay-Joof
Fatou
F
Pinder
Margaret
M
Peshu
Norbert
N
Williams
Thomas N
TN
Marsh
Kevin
K
Molyneux
Malcolm E
ME
Taylor
Terrie E
TE
Rockett
Kirk A
KA
Kwiatkowski
Dominic P
DP
D000017:ABO Blood-Group System / Q000235:genetics*; D000349:Africa; D000483:Alleles; D000818:Animals; D005260:Female; D016368:Frameshift Mutation; D014644:Genetic Variation; D005838:Genotype; D016695:Glycosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D016778:Malaria, Falciparum / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D000017:ABO Blood-Group System; D016695:Glycosyltransferases