What is the cause of alpha-1-antitrypsin deficiency?
Everyone has two genes that make alpha-1-antitrypsin (AAT). You inherit one from your mother and one from your father. If you have children, you pass on one of your two genes to them. Which one you pass on to each child is random, like tossing a coin.
The gene which produces AAT in the normal way is called M. The gene which causes AAT deficiency is called Z. Because everyone inherits two genes, there are three possible combinations of these genes: MM, MZ or ZZ. These combinations are called genotypes.
- MM: If you have two M genes you’ll have a normal level of AAT in your blood. It’s estimated that roughly 93% of the population have the MM genotype.
- MZ: If you have one M gene and one Z gene, you’ll have a lower than normal level of AAT in your blood. Usually the level isn’t low enough to cause major problems – you’ll probably have enough AAT to protect against damage. You may be more susceptible to lung disease, but if you don’t smoke, this is rarely a problem. If you have the MZ genotype, you are a carrier – this means you can pass the Z gene on to your children.
- ZZ: If you inherit two Z genes you’ll have a very low level of AAT in your blood – only 10%-20% of what it should be. You’re at high risk of getting lung disease especially if you smoke.
The diagram below shows how two parents who are carriers (MZ) can pass on different genotypes to their children. The parents may be entirely healthy but notice that they could have a child with the ZZ genotype.
The next diagram is an example of what happens if one parent has alpha-1-antitrypsin deficiency (ZZ) and the other doesn’t (MM). All of their children will inherit one Z gene, so they’ll all be carriers. But they’ll also all inherit one M gene so they’re unlikely to be affected by AATD.
Although the Z gene is the most common genetic cause of AATD there are some other rarer versions of the genes that also cause lower than normal levels of AAT. For example, there’s a gene called S which produces AAT to a level about halfway between M and Z.
In some people the AAT gene is missing or does not work properly. These are referred to as Null genes. They are very rare making interpretation of inheritance very difficult, though M Null and Z Null combinations generally have the same effect on health as MZ and ZZ.
It’s important to remember that there are other things that influence how much you’ll be affected by smoking. Two people with AATD may have very different lung conditions. This may vary in families too.