Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin is a protein that protects the lungs and is made in the liver. The main deficiency variant (the Z variant) lowers its levels, and two copies can lead to early emphysema (much worse with smoking) and liver problems.

What the Z variant does

SERPINA1 makes alpha-1 antitrypsin, a protein the liver secretes to protect the lungs from neutrophil elastase, an enzyme released during inflammation that digests tissue if left unchecked. The Z variant changes one amino acid, and the misshapen protein polymerises inside liver cells instead of being released.

That single change causes damage at both ends. The lungs are left short of protection, which drives early emphysema, and the liver accumulates the protein it cannot export, which is why alpha-1 antitrypsin deficiency is also a cause of liver disease in both children and adults.

How strong the evidence is

ClinVar records this variant as pathogenic with 50 submitters, under alpha-1 antitrypsin deficiency and the PI Z designations. It is also visible at population scale: in a genome-wide study of 315,668 people including 26,432 with chronic lung disease, it was a clear signal for lung disease risk.

Frequency matches the clinical picture. In 1000 Genomes reference data around 3.8% of European-ancestry individuals carry one copy and roughly 1 in 2,400 carry two, and it is close to absent in East Asian samples. Prevalence surveys of the two-copy PiZZ genotype put it near 1 in 408 in Northern Europe and 1 in 944 in Western Europe.

One copy and two copies are different situations

Two copies, the PiZZ genotype, leaves alpha-1 antitrypsin at roughly 10% to 15% of normal levels and is the classic deficiency, with a real risk of emphysema starting decades earlier than usual, and of liver disease. Intravenous augmentation therapy exists for PiZZ-associated emphysema and slows its progression, which makes this one of the few genetic findings on this site with a specific treatment attached.

One copy, the PiMZ genotype, is common, occurring in roughly 2% to 5% of the general population. Carriers who have never smoked have close to ordinary lung outcomes. Carriers who smoke have a measurably increased risk of airflow obstruction and COPD compared with non-carriers, in more than one population studied.

Smoking is the modifier that matters

Across the whole range of SERPINA1 genotypes, tobacco smoke is what turns a protein shortage into lung damage, because smoking both increases the elastase burden and inactivates what little protective protein is present. In people with the Z variant, not smoking and avoiding smoky and dusty environments is the single most consequential thing available, and it matters more for a carrier than any other lifestyle factor on this page.

What this variant does not tell you

The S variant, the other common deficiency allele, is not read here, and the PiSZ combination carries an intermediate risk that this file cannot detect. Rarer null and deficient alleles are likewise invisible.

It also does not measure anything. Alpha-1 antitrypsin level in blood is a simple test, and it, together with phenotyping or genotyping in a clinical laboratory, is how the deficiency is actually diagnosed. Unexplained emphysema before 50, emphysema in a never-smoker, or unexplained liver disease are the usual clinical reasons to test.

What each rs28929474 genotype means

rs28929474 has three possible genotypes: CC, CT and TT.

Normal alpha-1 antitrypsin (rs28929474 CC). You don't carry the main deficiency variant, so your body makes normal levels of alpha-1 antitrypsin, a protein that protects the lungs. From what this variant shows your risk of alpha-1 antitrypsin deficiency is not raised.

Alpha-1 antitrypsin carrier (rs28929474 CT). You carry one copy of the main deficiency variant, so you make somewhat less of the lung-protecting protein alpha-1 antitrypsin. Most carriers stay healthy, but the risk of lung problems is a bit higher, and avoiding smoking is especially worthwhile. You can also pass the variant on.

Alpha-1 antitrypsin deficient (rs28929474 TT). You have two copies of the main deficiency variant, which gives much lower levels of alpha-1 antitrypsin, the protein that shields your lungs. This raises the risk of early emphysema, greatly worsened by smoking, and can affect the liver. It's worth discussing with a doctor, and staying away from smoke is the single most protective step.

Evidence & sources

Across global populations, fewer than 1% of people carry two copies of this variant, and about 97% carry none.

This variant appears in 1 published genetic study: PubMed 39024449.

Common questions

I carry one Z copy. Should I be worried? The main finding in the literature is that carriers who smoke have increased risk of airflow obstruction and COPD, while never-smoking carriers are close to the general population. So the answer is less about worry than about tobacco, and about mentioning the result if you ever develop unexplained breathlessness or liver test abnormalities.

Can alpha-1 antitrypsin deficiency be treated? Yes, for the lung disease. Intravenous augmentation therapy with pooled human alpha-1 antitrypsin is the specific treatment for PiZZ-associated emphysema and has been shown to slow progression, with the greatest benefit when it is started early. Liver involvement is managed differently, and both are specialist decisions.

Does this explain my breathlessness? Not on its own. A genotype cannot tell you your alpha-1 antitrypsin level or your lung function, and both are directly measurable. Persistent breathlessness deserves clinical assessment, and if you carry this variant it is worth mentioning, since alpha-1 antitrypsin deficiency is widely under-diagnosed.

Related

G6PD deficiency (favism) · Gaucher disease type 1 (carrier) · Hereditary hemochromatosis (HFE gene)