Position of human blood group O(H) and phenotype‐determining enzymes in growth and infectious disease

The human ABO(H) blood group phenotypes arise from the evolutionarily oldest genetic system found in primate populations. While the blood group antigen A is considered the ancestral primordial structure, under the selective pressure of life‐threatening diseases blood group O(H) came to dominate as the most frequently occurring blood group worldwide. Non‐O(H) phenotypes demonstrate impaired formation of adaptive and innate immunoglobulin specificities due to clonal selection and phenotype formation in plasma proteins. Compared with individuals with blood group O(H), blood group A individuals not only have a significantly higher risk of developing certain types of cancer but also exhibit high susceptibility to malaria tropica or infection by Plasmodium falciparum. The phenotype‐determining blood group A glycotransferase(s), which affect the levels of anti‐A/Tn cross‐reactive immunoglobulins in phenotypic glycosidic accommodation, might also mediate adhesion and entry of the parasite to host cells via trans‐species O‐GalNAc glycosylation of abundantly expressed serine residues that arise throughout the parasite's life cycle, while excluding the possibility of antibody formation against the resulting hybrid Tn antigen. In contrast, human blood group O(H), lacking this enzyme, is indicated to confer a survival advantage regarding the overall risk of developing cancer, and individuals with this blood group rarely develop life‐threatening infections involving evolutionarily selective malaria strains.