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 that does a lot in the body, so read on to learn more about how genetic variants in this gene can impact your health.
What is alpha-1 antitrypsin?
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.
Elastin and Elastase:
Certain cells in your lungs produce a protein called elastin. The 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. Gram-negative bacteria also produce the elastin protein. As a result, 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 – meaning it inhibits a protein that breaks down other proteins. Specifically, alpha-1 antitrypsin inhibits elastase so it won’t break down your lung cells.
Alpha-1 antitrypsin is predominately 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 be used by neutrophils to attack gram-negative bacteria in the lungs, but alpha-1 antitrypsin keeps it from damaging your own lung cells.
Elastase – beyond lung cells:
Other enzymes inhibited by alpha-1 antitrypsin:
The immune system response is a balancing act, and alpha-1 antitrypsin plays a role in preventing damage from our own immune response.
While the focus of much of the research over the last half-century has been on elastase and lung function, alpha-1 antitrypsin also inhibits proteinase 2, trypsin, casthespin G, and other enzyme factors.[ref] Additionally, alpha-1 antitrypsin neutralizes chymase and tryptase from mast cells. In the pancreas, alpha-1 antitrypsin protects beta cells from cell death due to capsase 3 (important in type 1 diabetes).[ref]
Inflammation, the immune system, and alpha-1 antitrypsin:
Alpha-1 antitrypsin has also shown to act as an anti-inflammatory molecule, inhibiting neutrophil superoxide production, preventing cell death in liver cells, and inhibiting monocyte activation.[ref]
Inflammation increases the liver’s production of alpha-1 antitrypsin. As neutrophils release elastase to combat bacterial infections, there is a response by the liver to increase the alpha-1 antitrypsin enzyme.[ref]
In the acute-phase response — the immune response immediately after an injury or infection — alpha-1 antitrypsin production increases four-fold. Alpha-1 antitryptase is activated by lipopolysaccharide (present on gram-negative bacteria), TNF-alpha, oxidative stress, IL-1, and IL-6.[ref]
Interestingly, alpha-1 antitrypsin plasma infusions (via IV) have shown to be effective for some people with autoimmune disorders (type 1 diabetes, Crohn’s, MS, fibromyalgia, RA) and chronic fatigue syndrome (ME/CFS).[ref]
COVID-19: Although lacking in clinical data, there are several reports that alpha-1 antitrypsin deficiency may increase the risk of severe COVID-19. Talk with your doctor and read through these references… [ref][ref][ref]
What is alpha-1 antitrypsin deficiency?
Alpha-1 antitrypsin deficiency is thought to be one of the most common hereditary diseases worldwide.
Certain mutations in the SERPINA1 gene can cause alpha-1 antitrypsin deficiency due to the alpha-1 antitrypsin protein not functioning appropriately.[ref]
In the lungs:
Without alpha-1, there can be too much elastase, causing damage to lung tissue by breaking down elastin. The damage occurs in the alveoli, the little sacs that are vital for exchanging oxygen and carbon dioxide.
When the alveoli lose some of their elasticity, it can cause problems with easily bringing in oxygen and moving out CO2.
Thus, 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.
In the liver:
The liver produces alpha-1 antitrypsin in response to signals from the body for illness (fever, inflammatory signals). Therefore, it counteracts the neutrophil’s production of elastase at a time when the neutrophils are actively combating an infection.[ref]
The folding of the alpha-1 antitrypsin protein can be affected by the SERPINA1 mutations. The misfolded protein can then get stuck in the liver, unable to be transported to the lungs. This can cause liver damage (in addition to lacking the enzyme in the lungs).
Heterozygous advantage: Taller with greater lung volume as a baby
When mutations that cause a genetic disease are much 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, thus passing along the mutation to offspring.[ref]
Common alpha-1 antitrypsin deficiency variants:
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The two, most common mutations for alpha-1 antitrypsin deficiency 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 produced in the liver. Because the shape of the protein is altered, the mutant alpha-1 antitrypsin gets stuck within the liver, unable to make it to the lungs. The mutant proteins 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.
Check your genetic data for rs28929474 (23andMe v4, v5; AncestryDNA *):
- T/T: two copies of Pi*Z mutation, alpha-1 antitrypsin levels often less than 30% of normal[ref]
- C/T: one copy of the Pi*Z mutation
- C/C: typical
Members: Your genotype for rs28929474 is —.
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]
Studies show on Pi*Z carriers show:
- 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 ]
- New research also shows carrying the Pi*Z allele is also linked to an increased risk of high blood pressure.[ref]
- Additionally, people with two copies of the Pi*Z mutation may be at risk for higher iron and ferritin levels.[ref]
- Carrying one or two copies of the Pi*Z mutation increases the risk of cirrhosis in people who have NAFLD (fatty liver)[ref][ref]
- The Pi*M allele is more frequent than average in people with asthma and with aspirin-exacerbated respiratory disease.[ref]
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] About 5% of Caucasians carry one copy of this mutation.
Check your genetic data for rs17580 (23andMe v4, v5; AncestryDNA *):
- A/A: two copies of Pi*S mutation
- A/T: one copy of the Pi*S mutation
- T/T: typical
Members: Your genotype for rs17580 is —.
Studies show on Pi*S carriers show:
- 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]
- The Pi*S allele is more frequent than average in people with asthma and with aspirin-exacerbated respiratory disease.[ref]
*All rs id data is given in the plus orientation to match with 23andMe and AncestryDNA genetic raw data format.
SERPINA1 Rare Mutations:
In addition to the above more common SERPINA1 variants, rare mutations in the gene can also cause alpha-1 antitrypsin deficiency.[ref]
Check your genetic data for rs28929473 (23andMe v4, v5):
- A/T: one copy of a Null mutation
- T/T: typical
Members: Your genotype for rs28929473 is —.
Check your genetic data for rs199422211 (23andMe v4, v5):
- A/T: one copy of a Null mutation
- T/T: typical
Members: Your genotype for rs199422211 is —.
Check your genetic data for rs28931572 (AncestryDNA):
- A/T: one copy of a Null mutation
- A/A: typical
Members: Your genotype for rs28931572 is —.
Check your genetic data for rs28931568 (23andMe v4, v5; AncestryDNA):
- T/T: Two copies of the Pi Mineral Springs mutation[ref]
- C/T: one copy of the Pi Mineral Springs mutation
- C/C: typical
Members: Your genotype for rs28931568 is —.
Check your genetic data for rs61761869 (23andMe v4, v5; AncestryDNA):
- A/A: Two copies of the Pi Procida mutation[ref]
- A/G: one copy of the Pi Procida mutation
- G/G: typical
Members: Your genotype for rs61761869 is —.
Interaction with other Genes:
Our genetic variants act together not only with environmental factors but also with other genetic changes. This is one reason why there is such variation in the effects of the SERPINA1 mutations.
TNF-alpha: 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):
- A/A: increased likelihood of having chronic bronchitis with Pi*Z mutation
- A/G: increased likelihood of having chronic bronchitis with Pi*Z mutation
- G/G: typical
Members: Your genotype for rs361525 is —.
GSTP1 gene: Decreased GSTP1 (glutathione s-transferase pi 1) in one study has links to increasing the risk of COPD in alpha-1 antitrypsin deficiency.
Check your genetic data for rs1695 (23andMe v4, v5; AncestryDNA):
- A/A: typical
- A/G: typical
- G/G: reduced function, increased risk of COPD in AAT deficiency[ref]
Members: Your genotype for rs1695 is —.
Hemochromatosis mutations: With the increase in iron and ferritin levels from SERPINA1 mutations, you should also check to see if you carry mutations in the HFE gene that can cause hemochromatosis (iron overload): Building Up Iron: Check your genetic data for hemochromatosis mutations
Fatty liver disease: People who carry the SERPINA1 mutations are at a higher risk of liver problems in conjunction with fatty liver disease (NAFLD). With fatty liver disease occurring now in an estimated half of the US population, this is something to take into consideration if you carry one of the SERPINA1 mutations. Check your genes for other fatty liver disease risk factors: Fatty Liver: Genetic variants that increase the risk of NAFLD
Cystic Fibrosis: Carrying a SERPINA1 mutation increases the risk of liver disease in cystic fibrosis patients. Check your genetic data for cystic fibrosis mutations.
Your doctor can run tests to see what your alpha-1 trypsin levels are. If you carry two copies of the mutation, you should definitely talk with your doctor about testing and about possible long-term implications for lung and liver function.
If you currently don’t have a doctor or if your doctor won’t order it, you can order the alpha-1 antitrypsin test yourself from online lab companies and then go get your blood drawn locally. For example, Ulta Lab Tests offers it for $49. (Shop around, lab test costs online vary a lot)
There are plasma AAT therapies available for alpha-1 antitrypsin deficiency, which your doctor can prescribe if needed.[ref]
If you are wondering what the serum levels of alpha-1 antitrypsin should be, check out Table 2 in this article.
This is one mutation where it would be a really good idea not to drink or smoke.
Additionally, occupations, where you are exposed to a lot of airborne particulate matter are not a good idea…
Here are a couple of excellent resources for more information:
The interaction with higher TNF levels is one that you may be able to target with supplements that inhibit TNF. (Talk with your doctor, of course, if you are on any medications.)
Natural TNF-alpha inhibitors include:
- Rosmarinic acid (found in rosemary, basil, holy basil, lemon balm, and perilla oil) is a natural TNF-alpha inhibitor.[ref] In addition to adding herbs to your food, holy basil can be found in a tea (called Tulsi tea) or as a supplement. Examine.com has good information on rosmarinic acid.
- Curcumin, found in turmeric, is a natural TNF-alpha inhibitor.[ref]
- Resveratrol is another natural flavonoid that has been shown in studies to decrease TNF. It is thought to work via increasing SIRT1.[ref][ref]
- Probiotics containing Bifidobacteria or Lactobacillus may decrease TNF-alpha levels.[ref] One study showed that B. adolescentis decreased TNF-alpha levels and had an antidepressant effect.[ref] In kids with celiac disease, Bifidobacterium breve BR03 decreased TNF-alpha levels.[ref] Lactobacillus Plantarum restores tight junctions (decrease leaky gut) in the intestines. It is also decreased TNF-alpha.[ref][ref]
- Glycine reduces TNF-alpha and inflammation.[ref] Glycine is an amino acid that is abundant in bone broth, collagen, and gelatin. My favorite way to increase my intake of glycine is to add gelatin or collagen powder to my coffee in the morning.
- Sufficient Magnesium: Low magnesium levels may play a role in higher TNF-alpha levels. Magnesium sulfate, in conjunction with thyroid medication, decreased TNF-alpha levels (animal study).[ref][ref]
- Luteolin: In a study of children with autism spectrum disorder, luteolin supplementation decreases the elevated TNF levels significantly. The supplement used in the study was NeuroProtek.[ref]
- Hesperidin, a natural flavonoid from citrus fruits, inhibits the release of TNF-alpha.[ref]
- Aged garlic extract in a study decreased TNF-alpha levels by 35%.[ref][ref] You can find aged black garlic at grocery stores, and it is available as a supplement online if you don’t like the taste of aged garlic.
Interactions with medications:
- Heavy NSAID usage can cause liver damage. Animal models of alpha-1 antitrypsin deficiency show that NSAIDs could increase the risk of liver damage.[ref]
Related Genes and Topics:
TNF-alpha: Inflammation and Your Genes
Do you feel like you are always dealing with inflammation? Joint pain, food sensitivity, etc? Perhaps you are genetically geared towards a higher inflammatory response. Tumor necrosis factor (TNF) is an inflammatory cytokine that acts as a signaling molecule in our immune system. In an acute inflammatory situation, TNF-alpha plays an essential role in protecting us.
Fatty Liver: Genetic variants that increase the risk of NAFLD
Non-alcoholic fatty liver disease (NAFLD) is now the leading cause of liver problems worldwide, bypassing alcoholic liver disease. It is estimated that almost half of the population in the US has NAFLD caused by a combination of genetic susceptibility, diet, and lifestyle factors.
CTLA-4: Autoimmune Genetic Risk
The CTLA4 gene codes for a protein that is important in the immune system. It acts as a checkpoint that can downregulate your immune system response. Genetic variants in the CTLA4 gene can increase your risk for several different autoimmune diseases.
Originally published 12/2019, updated 2/2021