![]() The secretions and tissues of a person with an active FUT2 (a secretor) can express A, B, H, and Le b antigens in those secretions according to the glycosyltransferase genes inherited. A and B antigens can only be formed in the tissues of patients with an active FUT2 by the action of alpha-glycosyltransferases capable of transferring N-acetyl D-galactosamine or D-galactose to carbon 3 of the same glycans ( Figure 1B). 28 The structure created in tissues by the combined action of FUT2 and FUT3 is the Le b antigen. 27 The product of the Le gene is an alpha 1,3/4 fucosyltransferase ( FUT3), which transfers L-fucose to carbon 4 of the penultimate N-acetyl-D-glucosamine residue of the same glycans. ![]() In the absence of an active FUT2 gene (nonsecretor), the structure created is the Le a antigen. The expression of ABH antigens in tissues and body fluids other than blood cells is regulated by the secretor gene ( FUT2), which encodes an alpha 1,2-fucosyltransferase capable of transferring L-fucose to carbon 2 of galactose (beta, 1-3) N-acetyl D-glucosamine–containing glycans. 25 A combination of selection against infectious diseases, such as plague and smallpox, and genetic drift and founder effects in small populations (resulting from migration patterns of early humans) may ultimately explain the allele frequencies observed today. As discussed previously, the A→O mutation was likely driven by malaria in Africa before the migration of early humans to Europe, and CCR Δ32 has been described in skeletons from the Bronze Age. 26 The mutations A→O and CCRΔ32 occurred much earlier in human evolution than the plague and smallpox epidemics of medieval times. 25 This proposal has also been questioned. More recent studies have linked the high frequency of the HIV-1 resistance mutation CCR5Δ32 in Europe with protection against smallpox and the Black Death. However, suggestions that smallpox selects against A, thereby explaining the high frequency of group A in Europe, and that the low frequency of O in ancient plague centers in Mongolia and the Middle East is also a reflection of selection are not supported by adequate data (Vogel et al, cited in Mourant et al 2(p18) Kreiger and Morton 24). 13 A similar hypothesis could explain the function of A and B antigens on vWF. 12 It is proposed that mutations like factor V Leiden lower the risk of hemorrhage and/or severe infections and thereby the risk of death during pregnancy. Such an argument has been made for the occurrence of the prothrombotic mutations factor V Leiden and prothrombin 20210G>A, which are commonly found in white humans dated as occurring 20 000 to 24 000 years ago toward the end of the last ice age. 11 These observations raise the possibility that a greater propensity for blood clot formation in non-O patients conferred a survival advantage to early humans. 9 A, B, and H blood group antigens are expressed on N-glycans of vWF and influence the half-life of the protein (10 hours for group O and 25 hours for non-O subjects), providing an explanation for the greater levels in non-O patients. 8, 10 The risk of VTE is probably related to the level of vWF and factor VIII because patients of group A2 have lower levels of these proteins than A1, B, and AB and have a lower risk of VTE. 8, 9 Non–group O patients have a greater risk of VTE than patients of group O and have greater levels of von Willebrand factor (vWF) and factor VIII. One of the most significant disease associations described for non-O (subjects of group A, B, or AB) versus O subjects is susceptibility to arterial and venous thromboembolism (VTE). Founder effects provide a more convincing explanation for the distribution of the D− phenotype and the occurrence of hemolytic disease of the fetus and newborn in Europe and Central Asia. Red cells lacking or having altered forms of blood group-active molecules are commonly found in regions of the world in which malaria is endemic, notably the Fy(a−b−) phenotype and the S-s− phenotype in Africa and the Ge− and SAO phenotypes in South East Asia. However, available evidence suggests surviving malaria is the most significant selective force affecting the expression of blood groups. There are clear examples of protection against infectious diseases from inheritance of polymorphisms in genes encoding and regulating the expression of ABH and Lewis antigens in bodily secretions particularly in respect of Helicobacter pylori, norovirus, and cholera infections. ![]() Advances in our understanding of the migration patterns of early humans from Africa to populate the rest of the world obtained through the use of Y chromosome and mtDNA markers do much to inform this debate. The relative contribution of founder effects and natural selection to the observed distribution of human blood groups has been debated since blood group frequencies were shown to differ between populations almost a century ago.
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