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hh, [1] or the Bombay blood group, is a rare blood type. This blood phenotype was first discovered in Bombay by Dr. Y. M. Bhende in 1952. It is mostly found in the Indian subcontinent (India, Bangladesh, Pakistan) and Iran.
The first person found to have the Bombay phenotype had a blood type that reacted to other blood types in a way never seen before. The serum contained antibodies that attacked all red blood cells of normal ABO phenotypes. The red blood cells appeared to lack all of the ABO blood group antigens and to have an additional antigen that was previously unknown. [1]
Individuals with the rare Bombay phenotype (hh) do not express H antigen (also called substance H), the antigen which is present in blood group O. As a result, they cannot make A antigen (also called substance A) or B antigen (substance B) on their red blood cells, whatever alleles they may have of the A and B blood-group genes, because A antigen and B antigen are made from H antigen. For this reason people who have Bombay phenotype can donate red blood cells to any member of the ABO blood group system (unless some other blood factor gene, such as Rh, is incompatible), but they cannot receive blood from any member of the ABO blood group system (which always contains one or more of A, B or H antigens), but only from other people who have Bombay phenotype. [1]
Receiving blood that contains an antigen which has never been in the patient's own blood causes an immune reaction due to the immune system of a hypothetical receiver producing immunoglobulins against that antigen—in the case of a Bombay patient, not only against antigens A and B, but also against H antigen.
In order to avoid complications during a blood transfusion, it is very important to detect Bombay phenotype individuals, but the usual tests for ABO blood group system would show them as group O. Since anti-H immunoglobulins can activate the complement cascade, it will lead to the lysis of red blood cells while they are still in the circulation, provoking an acute hemolytic transfusion reaction. This cannot be prevented unless those typing the blood and providing care are aware of the existence of the Bombay blood group and have the means to test for it.[ citation needed ]
This very rare phenotype is generally present in about 0.0004% (about 4 per million) of the human population, though in some places such as Mumbai (formerly Bombay) locals can have occurrences in as much as 0.01% (1 in 10,000) of inhabitants. Given that this condition is very rare, any person with this blood group who needs an urgent blood transfusion will probably be unable to get it, as no blood bank would have any in stock. Those anticipating the need for blood transfusion may bank blood for their own use, but this option is not available in cases of accidental injury. For example, by 2017 only one Colombian person was known to have this phenotype, and blood had to be imported from Brazil for a transfusion. [2] In 2023, it was reported that only three registered Brazilians nationwide possessed this phenotype. [3]
Biosynthesis of the H, A and B antigens involves a series of enzymes (glycosyl transferases) that transfer monosaccharides. The resulting antigens are oligosaccharide chains, which are attached to lipids and proteins that are anchored in the red blood cell membrane. The function of the H antigen, apart from being an intermediate substrate in the synthesis of ABO blood group antigens, is not known, although it may be involved in cell adhesion. People who lack the H antigen do not suffer from deleterious effects, and being H-deficient is only an issue if they need a blood transfusion, because they would need blood without the H antigen present on red blood cells.[ citation needed ]
The specificity of the H antigen is determined by the sequence of oligosaccharides. More specifically, the minimum requirement for H antigenicity is the terminal disaccharide fucose-galactose, where the fucose has an alpha(1-2)linkage. This antigen is produced by a specific fucosyl transferase (Galactoside 2-alpha-L-fucosyltransferase 2) that catalyzes the final step in the synthesis of the molecule. Depending upon a person's ABO blood type, the H antigen is converted into either the A antigen, B antigen, or both. If a person has group O blood, the H antigen remains unmodified. Therefore, the H antigen is present more in blood type O and less in blood type AB.
Two regions of the genome encode two enzymes with very similar substrate specificities: the H locus (FUT1) which encodes the fucosyl transferase and the Se locus (FUT2) that instead indirectly encodes a soluble form of the transferase, which is found in bodily secretions. Both genes are on chromosome 19 at q.13.3. — FUT1 and FUT2 are tightly linked, being only 35 kb apart. Because they are highly homologous, they are likely to have been the result of a gene duplication of a common gene ancestor.
The H locus contains four exons that span more than 8 kb of genomic DNA. Both the Bombay and para-Bombay phenotypes are the result of point mutations in the FUT1 gene. At least one functioning copy of FUT1 needs to be present (H/H or H/h) for the H antigen to be produced on red blood cells. If both copies of FUT1 are inactive (h/h), the Bombay phenotype results. The classical Bombay phenotype is caused by a Tyr316Ter mutation in the coding region of FUT1. The mutation introduces a stop codon, leading to a truncated enzyme that lacks 50 amino acids at the C-terminal end, rendering the enzyme inactive. In Caucasians, the Bombay phenotype may be caused by a number of mutations. Likewise, a number of mutations have been reported to underlie the para-Bombay phenotype. The Se locus contains the FUT2 gene, which is expressed in secretory glands. Individuals who are "secretors" (Se/Se or Se/se) contain at least one copy of a functioning enzyme. They produce a soluble form of H antigen that is found in saliva and other bodily fluids. "Non-secretors" (se/se) do not produce soluble H antigen. The enzyme encoded by FUT2 is also involved in the synthesis of antigens of the Lewis blood group.
Bombay phenotype occurs in individuals who have inherited two recessive alleles of the H gene (i.e. their genotype is hh). These individuals do not produce the H carbohydrate that is the precursor to the A and B antigens, meaning that individuals may possess alleles for either or both of the A and B alleles without being able to express them. Because both parents must carry this recessive allele to transmit this blood type to their children, the condition mainly occurs in small closed-off communities where there is a good chance of both parents of a child either being of Bombay type, or being heterozygous for the h allele and so carrying the Bombay characteristic as recessive. Other examples may include noble families, which are inbred due to custom rather than local genetic variety.
In theory, the maternal production of anti-H during pregnancy might cause hemolytic disease in a fetus (HDN) who did not inherit the mother's Bombay phenotype. In practice, cases of HDN caused in this way have not been described. This may be possible due to the rarity of the Bombay phenotype but also because of the IgM produced by the immune system of the mother. Since IgMs are not transported across the microscopic placental blood vessels (IgG is the only immunoglobulin capable of crossing placenta) they cannot reach the blood stream of the fetus to provoke the expected acute hemolytic reaction.
An allele, or allelomorph, is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.
A blood type is a classification of blood, based on the presence and absence of antibodies and inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates, glycoproteins, or glycolipids, depending on the blood group system. Some of these antigens are also present on the surface of other types of cells of various tissues. Several of these red blood cell surface antigens can stem from one allele and collectively form a blood group system.
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and the second is called recessive. This state of having two different variants of the same gene on each chromosome is originally caused by a mutation in one of the genes, either new or inherited. The terms autosomal dominant or autosomal recessive are used to describe gene variants on non-sex chromosomes (autosomes) and their associated traits, while those on sex chromosomes (allosomes) are termed X-linked dominant, X-linked recessive or Y-linked; these have an inheritance and presentation pattern that depends on the sex of both the parent and the child. Since there is only one copy of the Y chromosome, Y-linked traits cannot be dominant or recessive. Additionally, there are other forms of dominance, such as incomplete dominance, in which a gene variant has a partial effect compared to when it is present on both chromosomes, and co-dominance, in which different variants on each chromosome both show their associated traits.
The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes. For human blood transfusions, it is the most important of the 44 different blood type classification systems currently recognized by the International Society of Blood Transfusions (ISBT) as of December 2022. A mismatch in this serotype can cause a potentially fatal adverse reaction after a transfusion, or an unwanted immune response to an organ transplant. Such mismatches are rare in modern medicine. The associated anti-A and anti-B antibodies are usually IgM antibodies, produced in the first years of life by sensitization to environmental substances such as food, bacteria, and viruses.
The term human blood group systems is defined by the International Society of Blood Transfusion (ISBT) as systems in the human species where cell-surface antigens—in particular, those on blood cells—are "controlled at a single gene locus or by two or more very closely linked homologous genes with little or no observable recombination between them", and include the common ABO and Rh (Rhesus) antigen systems, as well as many others; 44 human systems are identified as of 31 December 2022.
The Kell antigen system is a human blood group system, that is, a group of antigens on the human red blood cell surface which are important determinants of blood type and are targets for autoimmune or alloimmune diseases which destroy red blood cells. The Kell antigens are K, k, Kpa, Kpb, Jsa and Jsb. The Kell antigens are peptides found within the Kell protein, a 93-kilodalton transmembrane zinc-dependent endopeptidase which is responsible for cleaving endothelin-3.
The Kidd antigen system are proteins found in the Kidd's blood group, which act as antigens, i.e., they have the ability to produce antibodies under certain circumstances. The Jk antigen is found on a protein responsible for urea transport in the red blood cells and the kidney. They are important in transfusion medicine. People with two Jk(a) antigens, for instance, may form antibodies against donated blood containing two Jk(b) antigens. This can lead to hemolytic anemia, in which the body destroys the transfused blood, leading to low red blood cell counts. Another disease associated with the Jk antigen is hemolytic disease of the newborn, in which a pregnant woman's body creates antibodies against the blood of her fetus, leading to destruction of the fetal blood cells. Hemolytic disease of the newborn associated with Jk antibodies is typically mild, though fatal cases have been reported.
The Rh blood group system is a human blood group system. It contains proteins on the surface of red blood cells. After the ABO blood group system, it is the most likely to be involved in transfusion reactions. The Rh blood group system consisted of 49 defined blood group antigens in 2005. As of 2023, there are over 50 antigens among which the five antigens D, C, c, E, and e are the most important. There is no d antigen. Rh(D) status of an individual is normally described with a positive (+) or negative (−) suffix after the ABO type. The terms Rh factor, Rh positive, and Rh negative refer to the Rh(D) antigen only. Antibodies to Rh antigens can be involved in hemolytic transfusion reactions and antibodies to the Rh(D) and Rh antigens confer significant risk of hemolytic disease of the newborn.
The MNS antigen system is a human blood group system based upon two genes on chromosome 4. There are currently 50 antigens in the system, but the five most important are called M, N, S, s, and U.
The Lewis antigen system is a human blood group system. It is based upon two genes on chromosome 19: FUT3, or Lewis gene; and FUT2, or Secretor gene. Both genes are expressed in glandular epithelia. FUT2 has a dominant allele which codes for an enzyme and a recessive allele which does not produce a functional enzyme. Similarly, FUT3 has a functional dominant allele (Le) and a non-functional recessive allele (le).
The Ii antigen system is a human blood group system based upon a gene on chromosome 6 and consisting of the I antigen and the i antigen. The I antigen is normally present on the cell membrane of red blood cells in all adults, while the i antigen is present in fetuses and newborns.
Galactoside 2-alpha-L-fucosyltransferase 2 is an enzyme that in humans is encoded by the FUT2 gene. It affects the secretor status of ABO antigens.
Galactoside 2-alpha-L-fucosyltransferase 1 is an enzyme that in humans is encoded by the FUT1 gene.
Histo-blood group ABO system transferase is an enzyme with glycosyltransferase activity, which is encoded by the ABO gene in humans. It is ubiquitously expressed in many tissues and cell types. ABO determines the ABO blood group of an individual by modifying the oligosaccharides on cell surface glycoproteins. Variations in the sequence of the protein between individuals determine the type of modification and the blood group. The ABO gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Cis AB is a type of rare mutation in the ABO gene. It happens when the transferase allele contains a mix of amino acids from either A or B alleles, producing a bifunctional enzyme that can produce both types of antigens, usually with one weaker than the other. This results in a serum test result much like the standard, separate (trans) AB phenotype, although the weaker antigen can occasionally fail to be detected. It complicates the basic inheritance pattern and blood-transfusion compatibility matching for ABO blood typing.
Secretor status refers to the presence or absence of water-soluble ABO blood group antigens in a person's bodily fluids, such as saliva, tears, breast milk, urine, and semen. People who secrete these antigens in their bodily fluids are referred to as secretors, while people who do not are termed non-secretors. Secretor status is controlled by the FUT2 gene, and the secretor phenotype is inherited in an autosomal dominant manner, being expressed by individuals who have at least one functioning copy of the gene. The non-secretor phenotype (se) is a recessive trait. Approximately 80% of White people are secretors, while 20% are non-secretors. Non-secretors have reduced susceptibility to the most common strains of norovirus. Expression of the antigens in the Lewis blood group is also affected by secretor status: non-secretors cannot produce the Le(b) antigen.
The Vel blood group is a human blood group that has been implicated in hemolytic transfusion reactions. The blood group consists of a single antigen, the high-frequency Vel antigen, which is expressed on the surface of red blood cells. Individuals are typed as Vel-positive or Vel-negative depending on the presence of this antigen. The expression of the antigen in Vel-positive individuals is highly variable and can range from strong to weak. Individuals with the rare Vel-negative blood type develop anti-Vel antibodies when exposed to Vel-positive blood, which can cause transfusion reactions on subsequent exposures.
The Junior blood group system is a human blood group defined by the presence or absence of the Jr(a) antigen, a high-frequency antigen that is found on the red blood cells of most individuals. People with the rare Jr(a) negative blood type can develop anti-Jr(a) antibodies, which may cause transfusion reactions and hemolytic disease of the newborn on subsequent exposures. Jr(a) negative blood is most common in people of Japanese heritage.
Blood compatibility testing is conducted in a medical laboratory to identify potential incompatibilities between blood group systems in blood transfusion. It is also used to diagnose and prevent some complications of pregnancy that can occur when the baby has a different blood group from the mother. Blood compatibility testing includes blood typing, which detects the antigens on red blood cells that determine a person's blood type; testing for unexpected antibodies against blood group antigens ; and, in the case of blood transfusions, mixing the recipient's plasma with the donor's red blood cells to detect incompatibilities (crossmatching). Routine blood typing involves determining the ABO and RhD type, and involves both identification of ABO antigens on red blood cells and identification of ABO antibodies in the plasma. Other blood group antigens may be tested for in specific clinical situations.
The Lan blood group system is a human blood group defined by the presence or absence of the Lan antigen on a person's red blood cells. More than 99.9% of people are positive for the Lan antigen. Individuals with the rare Lan-negative blood type, which is a recessive trait, can produce an anti-Lan antibody when exposed to Lan-positive blood. Anti-Lan antibodies may cause transfusion reactions on subsequent exposures to Lan-positive blood, and have also been implicated in mild cases of hemolytic disease of the newborn. However, the clinical significance of the antibody is variable. The antigen was first described in 1961, and Lan was officially designated a blood group in 2012.