What is the cause of alpha-1-antitrypsin deficiency?
In this section, we cover how alpha-1-antitrypsin deficiency can happen, by explaining how the condition is genetically passed on.
Everyone has 2 genes that make alpha-1-antitrypsin (AAT). You inherit 1 from your mother and 1 from your father. If you have children, you pass on 1 of your 2 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 main gene which causes AAT deficiency is called Z. Because everyone inherits 2 genes, there are 3 possible combinations of these genes: MM, MZ or ZZ. These combinations are called genotypes. There is another gene which causes a milder AAT deficiency, called S. In general, the S gene only causes a low AAT level when combined with the Z gene (SZ genotype)
- MM: If you have two M genes, you’ll have a normal level of AAT in your blood. It’s estimated that 90-95% 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 2 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.
- SZ: If you inherit a S gene and a Z gene you have a milder form of AAT deficiency. There is a lower risk of lung disease compared to ZZ patients, and smoking is the major risk factor for getting lung problems.
Risk of AATD if both parents are carriers
This diagram shows how 2 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.
Risk of AATD if one parent has AATD, and the other doesn’t
This 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.
There are also some other possible genotypes linked to AATD. In some people the AAT gene is missing or does not work properly. These are referred to as Null genes. They are very rare, so it is hard to be very clear about their effects and how they are inherited. But 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.