ABO blood group system

History of discoveries of the blood types

The ABO blood group system is widely credited to have been discovered by the Austrian scientist Karl Landsteiner, who identified the O, A, and B blood types in 1900. Landsteiner originally described the O blood type as type "C", and in parts of Europe it is rendered as "0" (zero), signifying the lack of A or B antigen. Landsteiner was awarded the Nobel Prize in Physiology or Medicine in 1930 for his work. Alfred von Decastello and Adriano Sturli discovered the fourth type, AB, in 1902.

Due to inadequate communication at the time, it was subsequently found that the Czech serologist Jan Janský had independently pioneered the classification of human blood into four groups in 1907, but Landsteiner's independent discovery had been accepted by the scientific world while Janský remained then in relative obscurity. However, in 1921 an American medical commission acknowledged Janský's classification. Jan Janský is nowadays credited with the first classification of blood into the four types (I, II, III, IV).

Janský's classification remains in use today. In Russia and states of the former USSR blood types O, A, B, and AB are respectively designated I, II, III, and IV. The designation A and B with reference to blood groups was proposed by Ludwik Hirszfeld.

In America, W.L. Moss published his own (very similar) work in 1910.

Ludwik Hirszfeld and E. von Dungern discovered the heritability of ABO blood groups in 1910–11. Felix Bernstein demonstrated the correct blood group inheritance pattern of multiple alleles at one locus in 1924. Watkins and Morgan, in England, discovered that the ABO epitopes were conferred by sugars, to be specific, N-acetylgalactosamine for the A-type and galactose for the B-type. After much published literature claiming that the ABH substances were all attached to glycosphingolipids, Finne et al. (1978) found that the human erythrocyte glycoproteins contain polylactosamine chains that contains ABH substances attached and represent the majority of the antigens. The main glycoproteins carrying the ABH antigens were identified to be the Band 3 and Band 4.5 proteins and glycophorin. Later, Yamamoto's group showed the precise glycosyl transferase set that confers the A, B and O epitopes.

Antigens

The central principle of the ABO system is that antigens – in this instance, sugars physically exposed on the exterior of red blood cells – differ between individuals, who have immunological tolerance only toward what occurs in their own bodies. As a result, many humans express isoantibodies – antibodies against isoantigens, natural components present in the bodies of other members of the same species but not themselves. Isoantibodies may be present against the A and/or B antigens in people who do not themselves have the same antigens in their own blood. These antibodies act as haemagglutinins, which cause blood cells to clump and break apart if they carry the foreign antigens. This harsh response, though an adaptive reaction useful against infection, can cause death when large amounts of such cells are encountered after a blood transfusion, a circumstance not encountered in natural selection prior to modern history. Because A and B antigens are chemically modified from a precursor form that is also present in type O individuals, people with type A and B antigens can accept blood from type O individuals.

Anti-A and anti-B antibodies (called isohaemagglutinins), which are not present in the newborn, appear in the first years of life. Anti-A and anti-B antibodies are usually IgM type, which are not able to pass through the placenta to the fetal blood circulation. O-type individuals can produce IgG-type ABO antibodies.

The precursor to the ABO blood group antigens, present in people of all common blood types, is called the H antigen. Individuals with the rare Bombay phenotype (hh) do not express antigen H on their red blood cells. As the H antigen serves as a precursor for producing A and B antigens, the absence of the H antigen means that the individuals also lack A or B antigens as well (similar to O blood group). However, unlike O group, the H antigen is absent, hence the individuals produce isoantibodies to antigen H as well as to both A and B antigens. If they receive blood from someone with O blood group, the anti-H antibodies will bind to the H antigen on the red blood cells ('RBC') of the donor blood and destroy the RBCs by complement-mediated lysis. Therefore, people with Bombay phenotype can receive blood only from other hh donors (although they can donate as though they were type O). Some individuals with the blood group A1 may also be able to produce anti-H antibodies due to the complete conversion of all the H antigen to A1 antigen.

Production of the H antigen, or its deficiency in the Bombay phenotype, is controlled at the H locus on chromosome 19. The H locus is not the same gene as the ABO locus, but it is epistatic to the ABO locus, providing the substrate for the A and B alleles to modify. The H locus contains three exons that span more than 5 kb of genomic DNA, and encodes the fucosyltransferase that produces the H antigen on RBCs. The H antigen is a carbohydrate sequence with carbohydrates linked mainly to protein (with a minor fraction attached to ceramide moiety). It consists of a chain of β-D-galactose, β-D-N-acetylglucosamine, β-D-galactose, and 2-linked, α-L-fucose, the chain being attached to the protein or ceramide.

The ABO locus, which is located on chromosome 9, contains seven exons that span more than 18 kb of genomic DNA. Exon 7 is the largest and contains most of the coding sequence. The ABO locus has three main alleleic forms: A, B, and O. The A allele encodes a glycosyltransferase that bonds α-N-acetylgalactosamine to the D-galactose end of the H antigen, producing the A antigen. The B allele encodes a glycosyltransferase that bonds α-D-galactose to the D-galactose end of the H antigen, creating the B antigen.

In the case of the O allele, when compared to the A allele, exon 6 lacks one nucleotide (guanine), which results in a loss of enzymatic activity. This difference, which occurs at position 261, causes a frameshift that results in the premature termination of the translation and, thus, degradation of the mRNA. This results in the H antigen remaining unchanged in the case of O groups.

The majority of the ABO antigens are expressed on the ends of long polylactosamine chains attached mainly to band 3 protein, the anion exchange protein of the RBC membrane, and a minority of the epitopes are expressed on neutral glycosphingolipid.

Role of ABO antigens in transfusion medicine

For a blood donor and recipient to be ABO-compatible for a transfusion, the recipient must not have Anti-A or Anti-B antibodies that correspond to the A or B antigens on the surface of the donor's red blood cells (since the red blood cells are isolated from whole blood before transfusion, it is unimportant whether the donor blood has antibodies in its plasma). If the antibodies of the recipient's blood and the antigens on the donor's red blood cells do correspond, the donor blood is rejected. On rejection, the recipient may experience Acute hemolytic transfusion reaction (AHTR).

In addition to the ABO system, the Rh blood group system can affect transfusion compatibility. An individual is either positive or negative for the Rh factor; this is denoted by a '+' or '−' after their ABO type. Those with Rh-positive blood can safely receive both Rh-positive and Rh-negative blood, but those with Rh-negative blood should only receive Rh-negative blood. Rh-negative blood is used in emergencies when there is no time to test a person's Rh type. Because of this, the AB+ blood type is referred to as the "universal recipient", as there are neither Anti-B or Anti-A antibodies in its plasma, and can receive both Rh-positive and Rh-negative blood. Similarly, the O− blood type is called the "universal donor"; since its red blood cells have no A or B antigens and are Rh-negative, no other blood type will reject it.

Alteration of ABO antigens for transfusion

In April 2007, an international team of researchers announced in the journal Nature Biotechnology an inexpensive and efficient way to convert types A, B, and AB blood into type O. This is done by using glycosidase enzymes from specific bacteria to strip the blood group antigens from red blood cells. The removal of A and B antigens still does not address the problem of the Rhesus blood group antigen on the blood cells of Rhesus positive individuals, and so blood from Rhesus negative donors must be used. Patient trials will be conducted before the method can be relied on in live situations.

Another approach to the blood antigen problem is the manufacture of artificial blood, which could act as a substitute in emergencies.

Genetics

Blood groups are inherited from both parents. The ABO blood type is controlled by a single gene (the ABO gene) with three types of alleles inferred from classical genetics: i, I^A, and I^B. The I designation stands for isoagglutinogen, another term for antigen. The gene encodes a glycosyltransferase—that is, an enzyme that modifies the carbohydrate content of the red blood cell antigens. The gene is located on the long arm of the ninth chromosome (9q34).

The I^A allele gives type A, I^B gives type B, and i gives type O. As both I^A and I^B are dominant over i, only ii people have type O blood. Individuals with I^AI^A or I^Ai have type A blood, and individuals with I^BI^B or I^Bi have type B. I^AI^B people have both phenotypes, because A and B express a special dominance relationship: codominance, which means that type A and B parents can have an AB child. A couple with type A and type B can also have a type O child if they are both heterozygous (I^Bi,I^Ai) The cis-AB phenotype has a single enzyme that creates both A and B antigens. The resulting red blood cells do not usually express A or B antigen at the same level that would be expected on common group A₁ or B red blood cells, which can help solve the problem of an apparently genetically impossible blood group.

The table above summarizes the various blood groups that children may inherit from their parents. Genotypes are shown in the second column and in small print for the offspring: AO and AA both test as type A; BO and BB test as type B. The four possibilities represent the combinations obtained when one allele is taken from each parent; each has a 25% chance, but some occur more than once.

Historically, ABO blood tests were used in paternity testing, but in 1957 only 50% of American men falsely accused were able to use them as evidence against paternity. Occasionally, the blood types of children are not consistent with expectations—for example, a type O child can be born to an AB parent—due to rare situations, such as Bombay phenotype and cis AB.

Subgroups

The A blood type contains about 20 subgroups, of which A1 and A2 are the most common (over 99%). A1 makes up about 80% of all A-type blood, with A2 making up almost all of the rest. These two subgroups are not always interchangeable as far as transfusion is concerned, as some A2 individuals produce antibodies against the A1 antigen. Complications can sometimes arise in rare cases when typing the blood.

With the development of DNA sequencing, it has been possible to identify a much larger number of alleles at the ABO locus, each of which can be categorized as A, B, or O in terms of the reaction to transfusion, but which can be distinguished by variations in the DNA sequence. There are six common alleles in white individuals of the ABO gene that produce one's blood type:

The same study also identified 18 rare alleles, which generally have a weaker glycosylation activity. People with weak alleles of A can sometimes express anti-A antibodies, though these are usually not clinically significant as they do not stably interact with the antigen at body temperature.

Cis AB is another rare variant, in which A and B genes are transmitted together from a single parent.

Distribution and evolutionary history

The distribution of the blood groups A, B, O and AB varies across the world according to the population. There are also variations in blood type distribution within human subpopulations.

In the UK, the distribution of blood type frequencies through the population still shows some correlation to the distribution of placenames and to the successive invasions and migrations including Norsemen, Danes, Saxons, Celts, and Normans who contributed the morphemes to the placenames and the genes to the population.

The two common O alleles, O01 and O02, share their first 261 nucleotides with the group A allele A01. However, unlike the group A allele, a guanosine base is subsequently deleted. A premature stop codon results from this frame-shift mutation. This variant is found worldwide, and likely predates human migration from Africa. The O01 allele is considered to predate the O02 allele.

Some evolutionary biologists theorize that the I^A allele evolved first, followed by O (by the deletion of a single nucleotide, shifting the reading frame) and then I^B. This chronology accounts for the percentage of people worldwide with each blood type. It is consistent with the accepted patterns of early population movements and varying prevalent blood types in different parts of the world: for instance, B is very common in populations of Asian descent, but rare in ones of Western European descent. Another theory states that there are four main lineages of the ABO gene and that mutations creating type O have occurred at least three times in humans. From oldest to youngest, these lineages comprise the following alleles: A101/A201/O09, B101, O02 and O01. The continued presence of the O alleles is hypothesized to be the result of balancing selection. Both theories contradict the previously held theory that type O blood evolved first.

Origin theories

It is possible that food and environmental antigens (bacterial, viral, or plant antigens) have epitopes similar enough to A and B glycoprotein antigens. The antibodies created against these environmental antigens in the first years of life can cross-react with ABO-incompatible red blood cells that it comes in contact with during blood transfusion later in life. Anti-A antibodies are hypothesized to originate from immune response towards influenza virus, whose epitopes are similar enough to the α-D-N-galactosamine on the A glycoprotein to be able to elicit a cross-reaction. Anti-B antibodies are hypothesized to originate from antibodies produced against Gram-negative bacteria, such as E. coli, cross-reacting with the α-D-galactose on the B glycoprotein.

HIV can be neutralized in in vitro experiments using antibodies against blood group antigens specifically expressed on the HIV-producing cell lines.

However, it is more likely that the force driving evolution of allele diversity is simply negative frequency-dependent selection; cells with rare variants of membrane antigens are more easily distinguished by the immune system from pathogens carrying antigens from other hosts. Thus, individuals possessing rare types are better equipped to detect pathogens. The high within-population diversity observed in human populations would, then, be a consequence of natural selection on individuals.

Clinical relevance

The carbohydrate molecules on the surfaces of red blood cells have roles in cell membrane integrity, cell adhesion, membrane transportation of molecules, and acting as receptors for extracellular ligands, and enzymes. ABO antigens are found having similar roles on epithelial cells as well as red blood cells.

Bleeding and thrombosis (von Willebrand factor)

The ABO antigen is also expressed on the von Willebrand factor (vWF) glycoprotein, which participates in hemostasis (control of bleeding). In fact, having type O blood predisposes to bleeding, as 30% of the total genetic variation observed in plasma vWF is explained by the effect of the ABO blood group, and individuals with group O blood normally have significantly lower plasma levels of vWF (and Factor VIII) than do non-O individuals. In addition, vWF is degraded more rapidly due to the higher prevalence of blood group O with the Cys1584 variant of vWF (an amino acid polymorphism in VWF): the gene for ADAMTS13 (vWF-cleaving protease) maps to the ninth chromosome (9q34), the same locus as ABO blood type. Higher levels of vWF are more common amongst people who have had ischemic stroke (from blood clotting) for the first time. The results of this study found that the occurrence was not affected by ADAMTS13 polymorphism, and the only significant genetic factor was the person's blood group.

Disease risks

Compared to O group individuals, non-O group (A, AB, and B) individuals have a 14% reduced risk of squamous cell carcinoma and 4% reduced risk of basal cell carcinoma. Conversely, type O blood is associated with a reduced risk of pancreatic cancer. The B antigen links with increased risk of ovarian cancer. Gastric cancer has reported to be more common in blood group A and least in group O.

According to Glass, Holmgren, et al., those in the O blood group have an increased risk of infection with cholera, and those O-group individuals who are infected have more severe infections. The mechanisms behind this association with cholera are currently unclear in the literature.

ABO hemolytic disease of the newborn

ABO blood group incompatibilities between the mother and child does not usually cause hemolytic disease of the newborn (HDN) because antibodies to the ABO blood groups are usually of the IgM type, which do not cross the placenta. However, in an O-type mother, IgG ABO antibodies are produced and the baby can potentially develop ABO hemolytic disease of the newborn.

Clinical applications

In human cells, the ABO alleles and their encoded glycosyltransferases have been described in several oncologic conditions. Using anti-GTA/GTB monoclonal antibodies, it was demonstrated that a loss of these enzymes was correlated to malignant bladder and oral epithelia. Furthermore, the expression of ABO blood group antigens in normal human tissues is dependent the type of differentiation of the epithelium. In most human carcinomas, including oral carcinoma, a significant event as part of the underlying mechanism is decreased expression of the A and B antigens. Several studies have observed that a relative down-regulation of GTA and GTB occurs in oral carcinomas in association with tumor development. More recently, a genome wide association study (GWAS) has identified variants in the ABO locus associated with susceptibility to pancreatic cancer.

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the ABO gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

Pseudoscience

During the 1930s, connecting blood groups to personality types became popular in Japan and other areas of the world. There are some positive science studies.

Other popular but unsupported ideas include the use of a blood type diet, claims that group A causes severe hangovers, group O is associated with perfect teeth, and those with blood group A2 have the highest IQs. Scientific evidence in support of these concepts is nonexistent.