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What exactly is a 'blood group subtype'? Where does it come from? How is it inherited? These are some of the questions you may have if you have been tested and found to have a rare ABO subtype. Most typically in medical literature, an ABO subtype is called a 'subgroup' so that is the term used below.
Which ABO blood types have subgroups? It may be a surprise to find that A, B, O and AB have various subgroups. More of these are being found as techniques and equipment available for testing improve, some have been found only with the advent of molecular and genetic analysis. The A blood type appears to have the most variation in subgroups; several have been found for O's; B subgroups exist but are extremely rare; and AB's have a wide variety, as they can inherit all the possibilities of the A group.
In the United States, O is the most prevalent blood type, A is second, followed by B, and finally AB. The breakdown in Great Britain is very similar to the U.S. percentages. In Germany there are slightly more A's than O's; B's and AB's remain almost the same as U.S. percentages. In Japan and China A's, O's and B's are fairly evenly split, and the AB percentage increases over that found in European populations.
A blood types have the most variation in subgroup of any of the ABO blood types. There are about 20 different known subgroups. A1 and A2 individuals make up the vast majority of people with A blood type, all other subgroups equal less than 1% of A's.
These are the most important subgroups in the system. A1 equals approximately 80% of the entire A blood type population, and A2 makes up the remaining 20%, under current data. This means that all other subgroups must be rare. These figures show that A1's equal 32% of the entire population in the U.S., while A2's make up a full 8% of the population, or an amount double that of the entire AB population and nearly as large a group as all the B's in the U.S. One out of every 5 A's is an A2.
A1 red blood cells ( or 'erythrocytes') have about one million A antigens per cell. A2 red cells have only 250,000 A antigens per cell, or one-fourth the amount that A1 cells have.
The 'A' antigen on A1 and A2 subgroup blood cells is named 'Type 2 A' antigen; however, A1 subgroup blood cells also have two additional forms of antigen as well, 'Type 3 A' and 'Type 4 A', neither of which appear on A2 subgroup blood cells.
|A Antigens||Name and Location|
|Type 2A - on A1 and A2 cells|
|Type 3A - on A1 cells only|
|Type 4A - on A1 cells only|
|Red blood Cell||Ceramide||Glucose||Galactose||N-Acetyl Glucosamine||Fucose||N-Acetyl Galactosamine|
The H antigen (fucose) is a precursor of A and B antigens. It is present on the surface of all ABO types red blood cells - A, B, AB, and O. Adult O's have 1.7 million copies of H antigen per red blood cell. The A1 gene is a much better converter of H (or the 'O' antigen) than is the A2 gene. Therefore, A2 red cells have much more H antigen than do A1 red cells. The amount of H antigen on red cells of the common ABO groups from most to least is O > A2 > B > A2B > A1 > A1B.
A1 and A2 transferases differ in 'pH optima' (the pH - or alkalinity or acidity - at which an enzyme has maximum potency and efficiency). For A1 and A1B that pH is 6.0, while for A2 and A2B the optimum pH is 7.0 (7.0 is the 'neutral' point, and 6.0 is more acidic). The A2 tranferase functions best at a less acidic point than the A1 transferase.
|A1 Red Cell||A2 Red Cell|
This is most simply done by using the anti-A lectin, Dolichos biflorus. In the undiluted state, the lectin extract of Dolichos biflorus reacts as anti-A, since it agglutinates both A1 and A2 cells. When prepared at an appropriate dilution, however, the lectin reacts directly with A1 and A1B but not A2 or A2B red cells. If the red cells agglutinate, the person is subgroup A1. If no agglutintion takes place, the blood is not A1, and most probably is group A2 (Aint, an uncommon blood group, can also be agglutinated weakly by d. biflorus).
A3 is a fairly rare subgroup (1/1000). The main distinguishing feature of A3 red cells is MFA (mixed field agglutination) with anti-A and anti-A,B.
Ax (Ao) This is a rare subgroup (1/40,000). The main distinguishing features of Ax cells are: the A antigen is so weak it may only be detectable by using anti-A,B; and anti-A1 is usually present in the serum. If anti-A,B is not used, Ao cells may be mistyped as group O. Inheritance of the Ax phenotype does not always follow Mendelian rules and recent studies suggest that different alleles can result in this phenotype. Thus different mutations can give the result of the same blood subgroup. This means the Ax type is 'genetically heterogeneous,' different alleles can result in the same Ax subgroup expression. The Aint subgroup works the same way.
Am is a very rare subgroup. The main distinguishing features of Am cells are: no reaction with anti-A or anti-A,B in routine testing, and anti-A1 is not present in the serum.
Some of the other A subgroups are named A4, Abantu, Afinn, Aint (A1-A2 intermediate), Ael, Acl (various genotypes - AO1, AO1var, AO2), Aend, Ay, and Aweak. A subgroups found in African populations are most likely A2, or the rarer Aint, or Abantu.
An evolutionary relationship exists between A1 and A3 and Ael. A3 and Ael are mutations from the A1 cell. A similar evolutionary relationship exists between A2 and Aend and Aweak. Most individuals of these subgroups are 'heterozygous' for the A gene concerned: A3, Ax, Am, and Aend. This means they have two different alleles, they are usually not A3A3 for example, they might be A3A1. (An allele is one of two or more alternative forms of a gene at the same site in a chromosome).
As of mid-1999, unique N-acetylgalactosaminyltransferases have been encoded for several A subgroups (A1, A2, Ael, Ax) using PCR, and are available on the web at 'GenBank.' :
A1 and A2 are interchangeable as far as transfusion purposes are concerned. Both types will react well with anti-A, so a mistake in typing will usually not be made. There is a very small percentage of A2 (from 1-8%) and a larger group of A2B (22-35%) people who produce anti-A1, which gives an incorrect blood typing result for ABO type. Discrepancies of this sort must be resolved when a transfusion is required, it becomes critical at this point as failure to detect a weak subgroup of A may result in a patient or donor being mistyped as group AB or B. They may also be mistyped s group O, but this is not as serious a problem.
This table shows the way a subgroup may be tested against various antigens to determine exactly which one it is. A3 through Ael are considered 'weak' subgroups of A and you can see here that they are progressively less 'A-like' in reaction as they move toward the right-hand side of the table
Organs of different blood types are not used for transplant purposes due to immunological complications and decreased graft survival. Organs of group O can be used for other types as O is the universal donor, with no antibodies to other ABO blood types. Organs of A, B or AB individuals have antibodies against other types which presents a problem with graft survival. The A2 blood group subtype appears to be an exception to this rule however. A2 livers have been successfully transplanted into O type individuals.
Special thanks to Dr. Fumi Yamamoto, who answered my questions, and gave me a direction to start my search for information on ABO subtypes; and to Gill G, fellow 'A' for proofreading and comments.
Abstracts available on PubMed - Use the abstact Title in the search box:
Ann Hum Genet 1996 Jan;60 ( Pt 1):67-72
Racial heterogeneity of DNA polymorphisms linked to the A and the O alleles of the ABO blood group gene.
Blood 1996 Oct 1;88(7):2732-7
Molecular genetic analysis of variant phenotypes of the ABO blood group system.
Nature 1990 May 17;345(6272):229-33
Molecular genetic basis of the histo-blood group ABO system.
Blut 1989 Aug;59(2):157-61
Family study and frequency of blood group with strong B transferase accompanied by decreased A and H antigens.
Differences between A1/A2
Clin Chem 1992 Dec;38(12):2392-5
Use of synthetic H disaccharides as acceptors for detecting activities of UDP-GalNAc:Fuc alpha 1-->2Gal beta-R alpha 1-->3-N-acetylgalactosaminyltransferase in plasma samples from blood group A subgroups.
Biochem Biophys Res Commun 1992 Aug 31;187(1):366-74
Human histo-blood group A2 transferase coded by A2 allele, one of the A subtypes, is characterized by a single base deletion in the coding sequence, which results in an additional domain at the carboxyl terminal.
Blut 1985 Oct;51(4):251-8
Quantitation of antibody uptake on A group erythrocytes using immunoautoradiography and monoclonal IgM anti-A.
Hum Hered 1985;35(1):1-6
Uncertainty in identification of blood group A subtypes by agglutination test.
Biochem Biophys Res Commun 1984 Oct 30;124(2):523-9
Blood group A glycolipid (Ax) with globo-series structure which is specific for blood group A1 erythrocytes: one of the chemical bases for A1 and A2 distinction.
Am J Hum Genet 1982 Nov;34(6):919-24
An enzyme basis for blood type A intermediate status.
Vox Sang 1982 Nov;43(5):248-52
Elution of group-specific substance A from RBC of various subgroups of A and its effect on the agglutination of AX RBC.
Rev Fr Transfus Immunohematol 1976 Mar;19(1):67-88
[Properties of alpha-N-acetylgalactosaminyltransferases in sera of group A and weak A subjects].
Vox Sang 1994;66(3):231-6
Expression of A antigens on erythrocytes of weak blood group A subgroups.
Pinsho Ketsueki 1996 Feb;37(2):116-22
[Blood genotyping of patients with ABO-group transformations in hematologic disorders].
Vox Sang 1991;61(1):53-8
A new monoclonal anti-A antibody BIRMA-1. A potent culture supernatant which agglutinates Ax cells, but does not give undesirable reactions with B cells.
Am J Hum Genet 1988 Oct;43(4):422-8
Imbalance of blood group A subtypes and the existence of superactive B gene in Japanese in Hiroshima and Nagasaki.
Exp Clin Immunogenet 1986;3(4):187-94
Specificity of hemagglutinin of Falcata japonica which reacts with blood group active N-acetyl-D-galactosamine residues.
Dev Biol Stand 1984;57:43-7
Monoclonal antibodies against blood group antigens.
Vox Sang 1979;37(5):281-5
Activity of IgG and IgM ABO antibodies against some weak A (A3, Ax, Aend) and weak B (B3, Bx) red cells.
Vox Sang 1978;34(1):32-9
The nature of human blood group A3 erythrocytes.
Vox Sang 1975;29(5):390-3
A case of Ax phenotype transmitted by an A2B parent.
Transfus Med 1998 Sep;8(3):231-8
Heterogeneity of the blood group Ax allele: genetic recombination of common alleles can result in the Ax phenotype.
Transfusion 1996 Apr;36(4):309-13
Polymorphisms at the ABO locus in subgroup A individuals.
Vox Sang 1996;71(2):113-7
Evidence for a new type of O allele at the ABO locus, due to a combination of the A2 nucleotide deletion and the Ael nucleotide insertion.
Biochem Biophys Res Commun 1995 Nov 13;216(2):642-7
An Ael allele-specific nucleotide insertion at the blood group ABO locus and its detection using a sequence-specific polymerase chain reaction.
Vox Sang 1994;66(3):231-6
Expression of A antigens on erythrocytes of weak blood group A subgroups.
Sangre (Barc) 1994 Feb;39(1):49-51
[AEL: a rare variant of blood group A].
Vox Sang 1993;64(2):116-9
Molecular genetic analysis of the ABO blood group system: 1. Weak subgroups: A3 and B3 alleles.
Exp Clin Immunogenet 1989;6(2):143-9
A3 phenotype with A1 gene-specified enzyme character in serum.
Am J Hum Genet 1983 Nov;35(6):1117-25
The existence of atypical blood group galactosyltransferase which causes an expression of A2 character in A1B red blood cells.
Acta Haematol Pol 1978 Aug-Sep;9(3):193-7
[Rare erythrocyte phenotypes imitating weak variant of antigen A].
Transfusion 1976 Nov-Dec;16(6):580-93
Quantitative and thermodynamic studies of erythrocytic ABO antigens.
Ann Hum Biol 1975 Oct;2(4):379-86
Quantitative study of the ABO system in several groups of African populations.
CRC Crit Rev Clin Lab Sci 1975 Jun;6(1):19-45
Characteristics of African blood.
J Formos Med Assoc 1997 Dec;96(12):933-42 Blood groups and transfusion medicine in Taiwan. Lin M
Transplantation 1999 Apr 15;67(7):1071-3
Safe transplantation of blood type A2 livers to blood type O recipients.
Fishbein TM, et al.
Am J Surg 1992 Nov;164(5):541-4; discussion 544-5
Current experience with renal transplantation across the ABO barrier.
Nelson PW, Helling TS, Shield CF, Beck M, Bryan CF
J Mol Evol 2000 Mar;50(3):243-8
Ancient origin of the null allele se(428) of the human ABO-secretor locus (FUT2).
Koda Y, Tachida H, Soejima M, Takenaka O, Kimura H
Folia Med (Plovdiv) 1999;41(3):12-7
Expression of human blood group antigens A and B in stomach cells of C. carpio, C. auratus, R. ridibunda and H. sapiens.
Tomova E, Sarafian V, Ishev V I
Immunogenetics 1999 Jun;49(6):517-26
Comparison of allele O sequences of the human and non-human primate ABO system.
Kermarrec N, Roubinet F, Apoil PA, Blancher
Primate ABO glycosyltransferases: evidence for trans-species evolution.