Wednesday, February 21, 2007
ABO Blood Types
I described glycoproteins in a previous posting (Glycoproteins). Recall that these are proteins with long oligosaccharide chains attached to them. The oligosaccharides are normally put on as the proteins are being processed for export to the exterior of the cell. The process involves attaching a “core” oligosaccharide then modifying it once it is bound to the glycoprotein. The modifications include removing some sugar residues and adding others.
The cell surface of blood cells is covered with glycoproteins and the carbohydrate chains project out into the blood stream where they can easily be recognized by antibodies. We make antibodies to all sorts of things but the ones that attack our own cells are removed before they can do any harm. This anti-self screening of antibodies is one of the things that goes wrong in auto-immune diseases.
The proteins on the erythrocyte cell surface contain a wide variety of different oligosaccharides that are attached in various ways to the protein. However, it spite of this variation, there are a few structures that are very common. One of the most common “core” structures is something called H-antigen. It is composed of many different sugars but the outside end of the H-antigen structure always consists of a fucose (Fuc) residue, a galactose residue (Gal), and an N-acetylglucosamine (GlcNAc) residue.
In most primates, including humans, this core oligosaccharide is subsequently modified by adding an N-acetylgalactosamine (Monday’s Molecule #14) residue to form a branched structure at the end of the oligosaccharide (see diagram below). The enzyme that catalyzes this reaction is called N-acetylaminogalactosyltransferase or A enzyme. The gene for this enzyme is located on chromosome 9. The OMIN (Online Mendelian Inheritance in Man) entry for the ABO blood group is 110300. It contains a wealth of information on the topic.
If your red blood cells have oligosaccharides with a terminal GalNAc then you have blood type A. If you have a completely defective gene for A enzyme then your cells will have the unmodified H antigen structure and your blood type will be O. People with blood type A will not have antibodies to H antigen since this is the normal precursor to A antigen and there will always be some on the cell surface. In other words, the H antigen will be recognized as self.
Normal red blood cells are recognized as “self” so we don’t have antibodies against our own cells. However, we will have antibodies against the red blood cells of other people’s blood if their cell surface carbohydrates are different from ours. This is the basis of ABO blood group and it’s why we have to match blood types in a blood transfusion.
The ABO blood group was discovered over one hundred years ago by Karl Landsteiner (Nobel Laureate: Karl Landsteiner). The biochemical basis was only elucidated in the 1970’s when the technology for examining the carbohydrate structure of glycoproteins was worked out.
There’s an allele of the A enzyme gene that involves only a very small number of mutations but the result is to switch the enzyme from one that transfers GalNAc to one that transfers galactose (Gal). The variant enzyme is called B enzyme (galactosyltransferase) and the B antigen structure has a terminal galactose (Gal) instead of a terminal GalNAc.
If you are homozygous for the B allele on chromosome 9 then all of your red blood cells will have the B antigen oligosaccharide on their surface. You will not make antibodies against this structure because it’s “self.” You also won’t have antibodies against H-antigen for the reasons explained earlier. But you won’t recognize A antigen as self so your antibodies will attack any foreign cells that come from people with the normal wild-type allele (A).
People with blood type A will have antibodies against B antigen. They can receive blood from people with O blood type but they will reject blood from people with B blood type. You now have all the information you need to figure out who can give and receive blood from every possible combination of alleles: AA, AO, AB, BO, and OO.
There are no known natural effects of these differing blood types. People with A, B, AB and O phenotypes do not differ in fitness in any major way that we have been able to detect. This suggests that the complete absence of the enzyme (null mutation) is neutral in the current human population and so is the switch from one form of the enzyme to another. (Suggestions that blood type determines susceptibility to some infections are common in the scientific literature. Most of them have not held up. The best correlation is a possible association between blood type O and susceptibility to cholera. This looks pretty good but the cause-and-effect relationship is still up in the air.)
The ABO alleles seem to be segregating in the human population by random genetic drift. The O allele (non-functional enzyme) is the most common allele. The B allele is the least common—probably because it arose more recently. Some Native American populations are homogeneous for the O allele; in those populations everyone has blood type O. (For maps of the frequencies A and B alleles see Distribution of Blood Types.)