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Polymorphism

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Description

Subgroups of A are phenotypes that differ from others of the same ABO group with respect to the amount of A antigen carried on red blood cells (RBCs), and, in secretors, present in the saliva.

The two principal subgroups of A are A1 and A2.

RBCs of both react strongly with anti- A reagents in direct agglutination tests. The serologic distinction between A1, and A2 is based on results obtained in tests with reagent anti-A1, prepared from group B human serum or the lectin of Dolichos biflorus seeds.

Under prescribed testing conditions, anti-A1, reagents agglutinate A1, but not A2 RBCs. The RBCs of approximately 80% of group A or group AB persons are agglutinated by anti-A1, and, thus are classified as A1, or A1B. The remaining 20% whose RBCs are agglutinated by anti-A, but not by anti-A1, are called A2, or A2B.

Anti-A1 occurs in the serum of 1% to 8% of A2 persons and 22% to 35% of A2B persons. Anti-A1 can cause discrepancies in ABO testing and incompatibilities in crossmatches with A1, or A1B RBCs. It is considered to be clinically insignificant unless it reacts at 37 C. It is not necessary to test group A RBCs with anti A1, to confirm their subgroup status except when working with samples from people whose sera contain anti-A1.

Subgroups weaker than A2 occur infrequently and, in general, are characterized by decreasing numbers of A antigen sites on the red cells and a reciprocal increase in H antigen activity. The genes responsible constitute less than 1% of the total pool of A genes.

Classification of weak subgroups is generally based on the:

  • Degree of RBC agglutination by anti-A and anti-A1.
  • Degree of RBC agglutination by anti- A, B.
  • Degree of H reactivity of the RBCs.
  • Presence or absence of anti-A1 in the serum.
  • Presence of A and H substances in the saliva of secretors.

Rbcs of the Ax Ael, Aint or A3 subgroups are seen only infrequently in transfusion practice. Ax and Ael RBCs are readily recognized as subgroups of A by the discrepancies they produce between RBC and serum grouping tests. Ax RBCs are, in general, agglutinated by human anti-A,B but not by human anti-A. However, Ax RBCs react with some murine monoclonal anti-A reagents. Ael RBCs fail to react with anti-A or anti-A,B of any origin. Adsorption and elution studies are necessary to show that these rbcs carry the A antigen. RBCs of the Aint phenotype can be identified only if tests with anti-A1 are performed. Aint RBCs react more weakly than A1 RBCs with anti-A1, yet more strongly with anti-H than do A2 RBCs.

A3 RBCs produce a characteristic mixed-field pattern of small agglutinates among many free RBCs in tests with anti-A and anti-A,B. Weak subgroups of A such as Ax, Ael, and Aint, cannot be identified on the basis of blood grouping tests alone. Saliva studies and adsorption/elution studies must be performed.

A 539G > C mutation represents a new molecular basis for the A2 blood type. The amino acid substitution from arginine to proline may have effect on the expression of A antigen. (1)

There is extensive sequence heterogeneity underlying the major ABO alleles that produce normal blood groups A, B, AB and O when in correct combination with other alleles. Second, there is also extensive heterogeneity underlying the molecular basis of various alleles producing ABO subgroups such as A2, Ax and B3. There are over 70 ABO alleles reported to date and these alleles highlight the extensive sequence variation in the coding region of the gene.(2)

Discussion

The blood factor A is not always exactly the same in different individual human bloods. For a number of years it has been known that there were two main varieties of A which are designated as A, and A2. (3) Of these, the latter gives weaker reactions with the average anti-A reagent, and the former gives stronger reactions. Since this is not a textbook on serology, we will not go further into the nature of the differences between the two subgroups of the gene A.

Although peoples of European stock seem to differ serologically from the populations of all or nearly all the rest of the world, except possibly the African, in that they have the subgroup A2 of the blood group A and have a considerable amount of rh' and rhgenes, when and in what manner they acquired these differences is not easy to state. We do not at the present time know of any human (or even anthropoid) group with much more A2, proportionally, than the average European. Perhaps A2 has some selective disadvantage, and under the conditions of stringent selection in Asia was eliminated, before the ancestors of the American Indians left for this continent. In paleolithic European man the gene, although possibly somewhat inferior to A1, lingered on. But all this must be admitted to be in the highest degree conjectural.(4)

MatingChildren possible
A2 X OO, A2
A2 X A2O, A2
A2 X BO, A2, B, A2B
A2B x OA2, B
A2B X A2A2, B, A2B
A2B X BA2, B, A2B
A2B X A2BA2, B, A2B
A1B X OA1, B
A1B X A1A1,B, A2B, A1B
A1B X A2Al, B, A2B
A1B X A2BA1,B, A2B, A1B
A1B X BA1, B, A1B
A1B X A1BA1, B, A1B
A1 X OO, A1, A2
A1 X A1O, Al, A2
A1 X A2O, A1, A2
A1 X BO, A1, A2, B, A1B, A2B
A1 X A2BA1,A2, B, A1B, A2B

Table 1. Supposed mechanism of inheritance of subgroups.

The variations are expressed also in the group AB, so that we find two subgroups, A1B and A2B, where the difference in the A antigen is very much the same as it was in group A, save that in certain instances the A reaction in individuals of subgroup A2B may be weaker than in any individual of group A1, or even A2. It has been proposed (5,6) that the subgroups of A are inherited in the following way (Table 1) : instead of the gene series A, B, and O, suppose we have a series of four allelomorphs, A1, A2, B, and O, with A1 being dominant over A2, and A1, A2 and B all being dominant over O. This theory on the whole seems to fit most of the observations satisfactorily, although it does not account for the rather wide variability in sensitivity ro anti-A agglutinins in cells of individuals belonging to the subgroups A2 and A2B. (7)

Different alleles cause an imbalance in A2 and A2B phenotypes of the ABO blood group. In several populations, including the Japanese, the frequency of the A2B phenotype is significantly higher than expected based on the A2 phenotype frequency. The frequencies of A2-related alleles (*A105, *A106, *A107, *A111 and *R101) are different between the A2 and A2B phenotypes. In particular, a putative recombinant allele, *R101, was uncommon in the A2 but common in the A2B phenotype individuals. This allele was also detected in 4 of 401 (1%) unrelated A1 phenotype (AO genotype) individuals. *R101 is presumably expressed as phenotype A1 in *R101/*O heterozygous individuals, but as phenotype A2 in *R101/*B heterozygotes, thus giving rise to a high A2B phenotype frequency. (8)

Subgroups of the group A which are even weaker than A2, designated as A3 and A4, have been reported, but they are quite rare, and it seems unlikely that their existence is going to be of any particular importance to anthropologists. (9,10)

Studies to determine the relative proportion of A1 and A2 in different populations have been carried out, however, and the results depicted in Table 2. It is a striking fact that the subtype A2 does not seem to occur in the Australian aborigines, in China, Japan, in the Native Americans, or in the natives of the islands of the Pacific, in so far as can be determined from the somewhat sketchy studies made up to the present time. Simmons et al. (11) remark that these observations indicate that the subgroups of A will become a point of greater importance than heretofore in the study of races. Contrast, for example, the relatively high proportion of A2 in Negroes with its total absence in Papuans (12).

From a table such as Table 2, it is possible to calculate the gene frequencies p1, and p2, and if we were more certain of the mechanism of inheritance of the subgroups and of the correctness with which early workers distinguished A1 and A2 it would be desirable to do so. As it is, however, the most important thing one learns from the table is that nearly all non-European and non-African stocks possess no A2, i.e., p2= 0.

The situation in Africa is not yet fully understood, but in American Negroes at any rate, both A1 and A2 occur, the latter fairly frequently, and Wiener believes that an intermediate type of blood which is also found occasionally among whites, designated by him as A1,2, occurs much more commonly among Negroes. The expression of the subtype of the gene A which we knew as A2 seems to be chiefly a European and African characteristic, and it would enable us, if we wanted to, to mark off such populations from all others, on this basis alone. (13)

Unique A2 distributions

The Flittas

A remarkable isolate is that of the Flittas who live at Zemmora, southeast of Oran, and have a long history of fierce resistance to successive rulers of Algeria. They are probably of Berber origin, perhaps with some admixture at an early period, but they appear to have constituted a strict isolate for many hundreds of years. Their ABO frequencies are unique, with 18 per cent of A2 genes, the highest frequency known except in the Lapps of northern Scandinavia. The total A gene frequency reaches the high level of 30 per cent, and M at 57 per cent is also well above the general North Africa level. The presence of 26 per cent of cDe shows considerable Negro admixture, presumably long ago. The high A2 frequency remains a mystery—it is presumably the result of genetic drift or natural selection, but why should only three known populations, the Lapps, the Flittas, and the Nagas of Burma (with 17 per cent of A2) have evolved in this way, when the great majority of isolates in Europe and the Mediterranean area, including the Arabs of Arabia and the Berbers of the Atlas Mountains, have minimal O and low total A frequencies. It would be of great interest to carry out A1 A2 subgrouping on the other high A peoples of north Africa. (14)

The Lapps

The Lapps are an ethnic group living in northern Norway, Sweden, Finland, and north-western Russia. Some are reindeer herders and some are fishermen. They are on the whole of caucasoid appearance but with a very slight mongoloid tendency. They speak a Finno-Ugric language closely related to Finnish, but regarding this there are two points of view. One is that they formerly spoke a non-Finno-Ugric language now lost, and adopted Finnish which in the course of time became modified. The other is that their original language was a Finno-Ugric one, but belonging to the Ugric sub-family; this however became modified by the very large-scale adoption of words from the language of their neighbours, the Finns. This distinction is an important one with regard to their possible relationship to the Samoyeds.

The Lapps have been very thoroughly studied from the point of view of blood groups. They are almost unique in their high frequency of A and totally so in having the highest A2 gene frequency known, reaching 42 per cent in one group tested. In this respect they are super-Caucasoids, for the A2 gene is almost entirely confined to caucasoid and negroid populations in whom it is however mostly below 5 per cent and only extremely rarely exceeds 10 per cent. (15)

Links

References


1. Chen DP, Tseng CP, Wang WT, Sun CF. Identification of a novel A2 allele derived from the A transferase gene through a nucleotide substitution G539C.Vox Sang. 2005 Apr;88(3):196-9

2. Yip SP. Sequence variation at the human ABO locus. Ann Hum Genet. 2002 Jan;66(Pt 1):1-27

3. Landsteiner, K., and P. Levine, Proc. Soc. Exp. Biol. & Med., 24, 941942 (1927)

4. Boyd, ibid.

5. Thomsen, O., V. Friedenreich, and E. Worsaae, Acta Path. Et Microbiol. Scandinav., 7, 157 (1930)

6. Thomsen, O., V. Friedenreich, and E. Worsaae, Klin. Woch., 9, 67-69 (1930)

7. William C. Boyd. Genetics And The Races of Man, Little Brown and Company, Boston (1950)

8. Ogasawara K, Yabe R, Uchikawa M, Bannai M, Nakata K, Takenaka M, Takahashi Y, Juji T, Tokunaga K. Different alleles cause an imbalance in A2 and A2B phenotypes of the ABO blood group. Vox Sang. 1998;74(4):242-7

9. Schiff, F., and W. C. Boyd, Blood Grouping Technic. Interscience Publishers, New York, (1942)

10. Wiener, A. S., Blood Groups and Transfusion. Charles C Thomas, Springfield, 3rd ed., (1943)

11. Simmons, R. T., J. J. Graydon, and C. Ouwehand, Med. I. Australia, 32, 108-110 (1945)

12. Boyd, ibid.

13. Boyd, ibid.

14. Mourant, AE. Blood Relations, Blood Groups and Anthropology. Oxford University Press, Oxford, UK 1983.

15. Mourant, ibid.

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