The ABO Blood Group System, Rhesus Incompatibility and Disease.

1. Genetics of the ABO Blood Groups.

The ABO system is under the control of three genes, all the alleles being at one locus. Two alleles control A, A1 and A2. The antibody of one serum is incompatible with the cell antigen of another blood. Thus A possesses antibody B, group B has antibody A, and group AB has no antibodies. Group O has antibodies A and B. The groups A and B are dominant whereas O is recessive. Two genes therefore control the blood group. No child can possess an ABO antigen that is not in the parents. The A group is sub-divided, anti-A containing two antibodies, and these are alpha and alpha-1. Therefore alpha-1 is not present in A2 or A2B. Possible groups therefore are: A1A1; A1A2; A1B; A2B; A1o, A2O, plus of course BB; BO, and OO.

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Table 1ABO Serum Agglutination Reactions.

2. Secretors and non-secretors. 

In the ABO system, in the red cells, antigens and agglutinogens are present in alcohol soluble form. In some individuals they occur in a water soluble form and are thus present in other body secretions and fluids. The fluids they have been detected in are saliva, semen, amniotic fluid, tears, gastric juice, urine, and sweat. Group A secretes A, group B secretes B, and group O secretes substance H. Secretor status in the UK is 78% secrete and 22% are non-secretors.

The secretion of antigens in water soluble form is due to gene S. Gene S has a recessive allele s. Thus homozygous SS or heterozygous Ss are all secretors. Homozygous ss are all non-secretors. The inheritance of the S gene is independent of the ABO system, therefore there is no linkage.

3. Geographical distribution.

Variation occurs but is continuous in form. There is some regional heterogeneity. The world distribution shows considerable variation. [Kopec: Distribution of ABO Blood Groups in the UK. OUP]. ABO is distinguishable in apes with chimps showing A and O, Orangs and Gibbons with A and B, and gorillas with near A and near B.

The ABO system was established early in human evolution and has been maintained ever since. The pattern of variability is consistent with genetic drift, due to spatial and temporal isolation of populations. Also random effects may have operated. This when selective effects have been excluded to allow the drift explanation. Selection effects include action against the heterozygotes in the form of Erythroblastosis foetalis or haemolytic disease of the newborn. Rhesus incompatibility between the mother and her foetus is expected to occur in about 9% of conceptions in Europeans. This is predicted on the basis of a frequency of Rh(-) female times Rh(+) male matings, and a relative frequency of homozygotes amongst Rh(+) fathers. Haemolytic disease of the newborn due to Rhesus incompatibility occurs in about 0.6% of European births. This is strongly associated between the incidence and parity with only about 5% of offspring with haemolythic disease being first born, some 40-50% of the first appearance in families occur at third or later births.

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Table 2. Geographical Variation for Blood Group Allele Frequencies.

4. Rhesus and ABO incompatibility.

ABO incompatibility between the foetus and its mother is expected to occur in some 20% of conceptions in Europeans. This is predicted from frequency of: O female x A male; O x B; O x AB; A x B; B x A; A x AB; and B x AB matings, with a relative frequency of homozygotes among A and B fathers. Only 4 to 13% of mothers with Rhesus haemolytic disease children are ABO incompatible with their offspring. This suggests ABO status protects against Rhesus incompatibility effects. Haemolytic disease due to ABO status alone occurs in about 0.1% of births in Europe. Incompatibility selection against heterozygotes in the absence of other balancing forces gives rise to an unstable equilibrium. When this equilibrium is unbalanced or disturbed the rarest of the polymorphic alleles will decline in frequency.

4.  Blood Groups and Disease susceptibility.

Group O show a preponderance towards peptic ulcers, and A towards stomach carcinomas. This is a statistical relationship. A also show a trend to thromboembolism. A association between infectious diseases and blood groups has also been considered. It is claimed that there exists an epidemiological relationship between some groups and plagues and smallpox.

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Table 3.  ABO and Secretor Polymorphisms and Disease Susceptibility.

5. Unlinked loci in the ABO system. 

Four other loci are involved in determining the specific antigenic specificity of the macromolecules of the ABO system, and these are H, Lewis (Le), Secretor (se) and ABO loci. Genes A and B can only modify the H-substance, and not its precursor. They are thus ineffective in the heterozygous hh. With regard to the soluble substances the H gene can probably only act in the presence of Se, and therefore ineffective in genetic sese.

Derived from lecture notes and course hand-outs at University of Oxford (1971-1974) and Oxford Polytechnic (1986).

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