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Blood Type Genetics and Associated Issues continued

In my last post about genetics and inheritance, I asked a question about a family:

a family comes into a clinic for their flu shots and it is found that mom had type AB blood, Dad has type O blood and they have three children with type A, B and type O blood, what are all five people’s probable genotypes and what is the problem?

 

                                                Genotype      Problem

Mom:AB                      IAIB

Dad: O                         ii

Child1: A                      IAi

Child2: B                     IBi

Child 3: O                    ii                  Oops! Where did this kid come from?

After a short discussion, it turns out that Child 3 belongs to one parent from a previous marriage. Which parent’s child is this? If the other parent was homozygous, what was that person’s genotype and phenotype for ABO blood type?

It turns out that blood is even more interesting than this. There is another major blood antigen that needs to be matched when doing transfusions. This antigen is called ‘Rh factor’ because it was initially found in Rhesus Macaques, a type of monkey with a lineage close to our own. Although there are a number of Rh antigens, we are typically referring to the one that elicits the strongest immune response, the D antigen. Blood types are commonly referred to as ‘positive’ if the individual has the D antigen allele or ‘negative’ if the individual does not have this allele.

Like the ABO blood types, the Rh allele is important because of the strong immune response against it after Rh- individuals are exposed to Rh+ blood. Note that this is different than the ABO types where antibodies already exist. People only generate ‘anti-Rh’ antibodies after a primary exposure to this blood type, much like when a person is vaccinated against a disease, exposure to disease-associated antigens initiates the immune response, which will be protective upon later exposures.

This sounds like I am spending too much time in the details, but they are important in this case. To illustrate, let’s discuss the most common situation where this is important:

A woman with type A- becomes pregnant from a man with type B+ blood type.

What ABO blood types are possible from this pairing? Depending upon the genotype of the parents, it could be anything (A,B,AB or O).

But we said that it would be dangerous for blood to mix between someone with A blood type, like the mother, and any type that contained the B antigen, possibly like the baby.  So, is this baby in danger?

Thankfully, not. The reason is because the antibodies that we naturally make against the A or B antigens are typically IgM, which are very large molecules that do not pass through the placenta to the baby.

Image

The larger IgM antibody cannot cross the placenta, but the smaller IgG antibodies can

 

What about the Rh antigen?

The Rh alleles interact in a typical dominant / recessive manner. As you might expect, Rh+ means that you express the protein, and this allele is dominant over Rh-, which means you don’t express this protein. Given this, we know that the mother must be Rh-/Rh- in order for her to have the ‘negative’ phenotype. The man has the ‘positive’ phenotype and therefore must be either Rh+/Rh- or Rh+/Rh+. Either way, the child has a good chance of being Rh+ as well (50% or 100% respectively).

Unlike the antibodies against A and B antigens, antibodies against Rh are typically smaller, IgG molecules. These are capable of crossing the placenta into the child’s blood and can be very dangerous. But also unlike the A and B antigens, anti-Rh antibodies don’t exist prior to exposure, so the mother will not likely have any of these antibodies during her first pregnancy with an Rh+ child.

Because of the nature of childbirth, it is possible that a mother will be exposed to her child’s blood during birth and she may develop antibodies against Rh at this time. But child #1 is already out, so he/she is safe. The difficulty occurs when the mother becomes pregnant with a second Rh+ child. At this time her anti-Rh antibodies can cross the placenta and cause hemolytic disease in the developing baby.

Fortunately, there is a good safety against this. A Johnson and Johnson subsidiary company, Ortho, makes an antibody cocktail called RhoGAM that is given at the 28th week of pregnancy and then again within 72 hours after delivery (now there are a number of similar drugs made by other companies as well). This cocktail contains antibodies that bind to and ‘hide’ any Rh antigen in the mother’s system. In this way, the mother’s immune system never ‘sees’ this antigen and doesn’t make antibodies against Rh, making it safe for her subsequent Rh+ children.1,2

References

  1. Pregnancy (rhesus negative women) – routine anti-D (review) (TA156) http://guidance.nice.org.uk/TA156
  2. Rh incompatability. http://www.nlm.nih.gov/medlineplus/ency/article/001600.htm
 
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Posted by on November 12, 2012 in Uncategorized

 

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A Second Look at Heredity

Continuing the discussion about heredity from where we left off…

Inheritance is not always as straightforward as a simple interaction of one dominant and one recessive allele for each trait. In this post, I‘ll cover the concept of co-dominance and what happens where there is more than one allele for a trait.

Perhaps the simplest explanation of this concept comes from the example of our blood types. In the early 20th century Karl Landsteiner and several other investigators independently discovered the ABO blood type distinctions. The problem was that following accidents involving significant blood loss, patients required transfusions of red blood cells (RBCs) in order for them to supply the body with significant oxygen and to drain it of excess carbon dioxide. Curiously, some transfusions worked, while others failed with fatal consequences.

The key was that some transfusions worked. If they all failed, then we would just assume that RBCs can’t be moved from one person to another. So there was a pattern that needed to be deciphered.

We know now that the ABO antigens are the result of enzymes which ‘decorate’ a specific protein, the H antigen, found on these cells. All RBCs have the H antigen, but it gets modified by an enzyme during its synthesis. This enzyme attaches –or decorates – carbohydrate molecules to the H antigen in specific ways. One form of this enzyme decorates the antigen in one way (producing the ‘A’ antigen), one form decorates it in another way (producing the ‘B’ antigen) and one form makes a non-functional enzyme that doesn’t attach any carbohydrate at all (the ‘O’ antigen).

RBCs with antigens on surface

What do these proteins and carbohydrates have to do with blood transfusions? Understanding this requires a simple understanding of the immune system. This system is in place to keep the body safe and free from pathogens (and cancer). It operates primarily by discriminating between two groups:

Self – Cells and cell products of the individual are effectively invisible to that individual’s own immune system (this is a simplification, but it will suffice here)

Non-Self – anything that is not recognized as self will be attacked by the immune system. Non-self consists of foreign particles, micro-organisms and even cancer cells (these are considered ‘altered-self’)

Because of the way the immune system operates, people with type A blood will not react to the ‘A antigen’, but will react to the ‘B antigen’. People with type B blood will not react to the ‘B antigen’, but will react to the ‘A antigen’. People with blood type O will have immune reactions against both A and B antigens. However, because type O blood does not have any unique antigen, no one’s immune system will react to it.

These immune attacks can be very severe if the body is infused with a significant amount of mismatched blood leading to a systemic inflammatory reaction and quite possibly death.

But back to our main focus – genetics. What does the ABO blood group have to do with inheritance? The answer is that this phenomenon is an excellent example of co-dominance and what it looks like when more than one allele occurs for a single trait.

The two antigens A and B result from the alleles IA and IB, respectively. These two alleles are co-dominant, which means that whenever an individual carries one of these alleles, they will express the phenotype. People who have the IA allele have type A blood because their RBCs have the A-antigen on the surface. People who have the IB allele have type B blood because their RBCs have the B-antigen on the surface. And People who have both the the IA allele and the IB allele have type AB blood because their RBCs have both the A- and B- antigens on the surface. The immune system of these people will not react to A or B antigens, and therefore can accept blood transfusions from all blood types.*

A third allele, i, is recessive to both IA and IB alleles because i does not encode a functional enzyme – this amounts to a null case.

One can see now how these three alleles interact with one another.  It may also be evident that  people who have type A blood may be either of ‘IA IA’ or IAi genotype.Consider a woman with blood type AB and a man with blood type O. What alleles do they carry and what blood types might their children have?

So, if a family comes into a clinic for their flu shots and it is found that mom had type AB blood, Dad has type O blood and they have three children with type A, B and type O blood, what are all five people’s probable genotypes and what is the problem?

Mom:AB

Dad: O

Child1: A

Child2: B

Child 3: O

*Again, I am over-simplifying. There is another antigen, Rh, that is also important for blood transfusions and cannot be ignored in the real world. We will get to that soon, but not in this post.

 
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Posted by on November 11, 2012 in Uncategorized

 

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