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

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 (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.

Association of ABO Blood Group and Malaria Parasitic Infection in Eiedbabkier, Sudan

“…The chance of havingmalaria infection in individuals with non-O blood groups was two times more than individuals showing blood O phenotypes (OR = 2.07), this is consistent with previous reports [14,15] , suggesting that individuals with blood groups A, B and AB are more susceptible to P. falciparum infection than those with O group.Our study contradicts with some other studies.Zerihun T. et al reported high frequencies of O blood group (51.3%) followed by A (23.5%), B (21.6%), and AB (3.3%) [16] .Singh et alhave reported that 'A', 'B' and 'O' groups are equally susceptible to malaria while 'AB' is less susceptible [17] . Parasitaemia seemed to be relatively high across all blood groups with groups A apparently recording the highest parasitic density.…”

Population genetics of malaria resistance in humans

“…Their conclusion is based primarily on the consistency between the worldwide distribution of ABO variants and historic presence of malaria, with the O allele more common in areas with historic malaria and the association of O genotypes with higher resistance to malaria and A and B genotypes with lower resistance in a number of studies (Uneke, 2007). In a large recent study, Fry et al (2008) showed in three African populations a strong association of O individuals with resistance to severe malaria and found that this effect was recessive, that is, AO and BO individuals were as likely to be susceptible as AA and BB individuals and that AB genotypes were the most susceptible. In addition, it appears that the O allele can protect against severe malaria by a mechanism of reduced rosetting (spontaneous binding of infected erythrocytes to uninfected erythrocytes) (Rowe et al, 2007).…”

“…In addition, it appears that the O allele can protect against severe malaria by a mechanism of reduced rosetting (spontaneous binding of infected erythrocytes to uninfected erythrocytes) (Rowe et al, 2007). Fry et al (2008) calculated F ST values for the ABO genomic region and found that, even with its polymorphism within populations, it was an outlier for low F ST over populations. They suggested that this similar variation over different populations is the result of similar long-standing balancing selection over populations, perhaps caused by infectious pathogens, including P. falciparum.…”

Blood group does not appear to affect longevity a pilot study in centenarians from Western Sicily

“…Nonetheless, some associations appear striking, including an increased risk of severe Plasmodium falciparum malaria in those with non-O alleles. (Fry et al 2008;Anstee, 2010). Furthermore, numerous studies showed a strong association of non-O blood group with arterial and venous thromboembolism due to the presence, in A/B subjects, of high levels of von Willebrand Factor and Factor VIII (Anstee, 2010).…”