A genetic mutation in the SERPINA1 gene causes alpha-1 antitrypsin deficiency. This increases a person’s susceptibility to COPD (chronic obstructive pulmonary disease) and, in some cases, cirrhosis of the liver.
As far as rare mutations go, the alpha-1 antitrypsin deficiency mutations are fairly common and pop-ups on 23andMe or AncestryDNA data more often than you would think. For a lot of people, it is one of those lightbulb moments of – such as ‘this is why Mom/Dad had COPD at a relatively young age’.
Alpha-1 antitrypsin is an enzyme produced in your body. The SERPINA1 (serine protease inhibitor 1) gene codes for the alpha-1 antitrypsin protein. Alpha-1 antitrypsin was named a while ago – before the function was fully understood – so its name is a bit misleading.
In your lungs, there is a protein called elastin that is produced by certain cells. Elastin increases the elasticity and strength of the lung tissue in the alveoli, which are the tiny air sacs where oxygen is exchanged with carbon dioxide.
Elastin, though, isn’t unique just to your lung cells. The elastin protein is also produced by Gram-negative bacteria, so your immune system (specifically the neutrophils), creates an enzyme called elastase to break apart the elastin in the outer membrane of the bacteria.
Elastase is great – when you need to get rid of bacteria. But you don’t want too much elastase hanging around, because it can also break down the elastin in the cells in your lungs.
Alpha-1 antitrypsin comes into play here. It is a protease inhibitor – which means that it inhibits a protein that breaks down other proteins. Specifically, alpha-1 antitrypsin inhibits elastase so that it won’t break down your lung cells.
Alpha-1 antitrypsin is made in the liver and then transported to the lungs. In the lungs, it deactivates elastase before it damages lung cells. Pretty neat system – elastase can attack gram-negative bacteria in the lungs, but alpha-1 antitrypsin keeps it from damaging your own lung cells.
Certain mutations in the SERPINA1 gene can cause alpha-1 antitrypsin deficiency due to the alpha-1 antitrypsin protein not functioning appropriately. Alpha-1 antitrypsin deficiency is thought to be one of the most common hereditary diseases worldwide. [ref]
Without alpha-1, there can be too much elastase, causing damage to lung tissue. The damage occurs in the alveoli. When the alveoli lose some of their elasticity, it can cause problems with easily bringing in oxygen and moving out CO2.
People who carry alpha-1 antitrypsin deficiency mutations are more likely to have COPD – chronic obstructive pulmonary disease.
COPD causes shortness of breath, wheezing, cough, and mucus production. Other terms for COPD include emphysema and chronic bronchitis.
As you can imagine, smoking is really bad for people with alpha-1 antitrypsin deficiency. Carriers of the alpha-1 antitrypsin deficiency mutations are at a much higher and earlier risk of COPD compared with smokers without the mutation.
The liver produces alpha-1 antitrypsin in response to signals from the body for illness (fever, inflammatory signals). This is so that it counteracts the neutrophil’s production of elastase at a time when the neutrophils are actively combating an infection. [ref ]
There are two mutations for alpha-1 antitrypsin deficiency that are more common. They are known as Pi*Z and Pi*S. The mutations cause differences in the alpha-1 antitrypsin enzyme, and there can be different outcomes based on which mutation a person carries.
If you are reading through the research on alpha-1 antitrypsin deficiency, the normal version of the gene is referenced as Pi*M.
The Pi*Z and Pi*S mutations cause the alpha-1 trypsin protein to be misfolded when it is produced in the liver. Because the shape of the protein is altered, the mutant alpha-1 antitrypsin will get stuck within the liver, unable to make it to the lungs. The mutant proteins that are stuck in the liver cells increase the risk of cirrhosis (liver damage/failure).
SERPINA Pi*Z mutation:
About 1% of Caucasian populations carry one copy of the SERPINA1 mutation referred to as Pi*Z.
In people with two copies of the Pi*Z mutation, both the lungs and the liver can be affected. Cirrhosis is a common complication, in addition to COPD. Infants with two copies of the Pi*Z are likely to have jaundice. [ref ]
People who carry one copy of the Pi*Z mutation are more likely to have COPD if they smoke. They are also likely to have decreased lung function.[ref ]
Check your genetic data for rs28929474 (23andMe v4, v5; AncestryDNA *):
SERPINA Pi*S mutation:
The Pi*S mutation also causes decreased alpha-1 antitrypsin. Carriers of the Pi*S mutation are at a higher risk for liver fibrosis. [ref ]
Check your genetic data for rs17580 (23andMe v4, v5; AncestryDNA *):
Carriers of one copy of the Pi*Z or Pi*S mutation are at a higher risk of having problems with lung function, especially in smokers.[ref ]
Carriers of one copy of the mutations are also at a higher risk of cirrhosis with heavy alcohol consumption.[ref ]
*All rs id data is given in the plus orientation to match with 23andMe and AncestryDNA genetic raw data format.
Our genetic variants act together not only with environmental factors but also with other genetic changes.
The TNF gene codes for the inflammatory cytokine, TNF-alpha, which is part of the body’s immune response system. Higher amounts of TNF-alpha can cause chronically increased inflammation. Researchers studied the TNF genetic variants in a group of people who have Alpha-1 Antitrypsin Deficiency and found that carrying a specific TNF variant doubled the likelihood of the carriers having chronic bronchitis. [ref]
Check your genetic data for rs361525 (23andMe v4, v5; AncestryDNA):
When mutations that cause a genetic disease are more common in the population than they statistically should be, researchers often check to see if there is an advantage for people who carry one copy of the mutation. For example, people who carry one copy of the sickle cell anemia mutation are more resistant to malaria. The sickle cell mutation is more commonly found in people who live in Africa, where malaria is highly prevalent. People who carry one copy of the sickle cell mutation are more likely to survive malaria, thus passing on the mutation to their children.
A study published in 2016 looked at several different genetic diseases to see if there was an advantage to carrying one copy of the mutation. For alpha-1 antitrypsin deficiency, the researchers found that carriers of one copy of the Pi*Z mutation tended to be taller (1.5cm on average) and also had greater initial lung volume. This could lead to a survival advantage for babies. [ref ]
Your doctor can run tests to see what your alpha-1 trypsin levels are. If you carry one copy of the mutation and drink or smoke, it would be a good idea to talk with your doctor.
Here are a couple of excellent resources for more information: