Alpha-1 Antitrypsin Deficiency From Raw DNA: Reading SERPINA1 Z and S

You can check the two main alpha-1 antitrypsin variants in your raw DNA: Z (rs28929474) and S (rs17580) in the SERPINA1 gene. Together they give your Pi type: MM (normal), MS, MZ, SS, SZ or ZZ. ZZ is alpha-1 antitrypsin deficiency, with a high risk of early emphysema (especially if you smoke) and liver disease. It's badly under-diagnosed, so this is one of the most useful findings a raw file holds. The free report at healthosx.com/dna reads both positions and gives you the Pi type in plain words.

What alpha-1 antitrypsin does

Alpha-1 antitrypsin (AAT) is a protein made in the liver that protects the lungs from an enzyme released by white blood cells. The Z variant makes AAT fold wrongly. It gets stuck in the liver, which can damage it, and too little reaches the lungs, which lets the enzyme break down lung tissue. The S variant lowers AAT levels more mildly.

Reading your file

On the plus strand that 23andMe and AncestryDNA use:

• rs28929474 (Z): T is the Z allele. CC means no Z, CT means one Z, TT means two.
• rs17580 (S): A is the S allele. TT means no S, AT means one S, AA means two.

Combine them: no Z and no S is MM. One Z alone is MZ. One Z plus one S is SZ, and so on.

What each type means

• MM: normal. Nothing to do.
• MS or SS: mildly lower AAT, usually without consequences. Not smoking is the lever.
• MZ: a carrier. Usually fine, but smoking and dust or fume exposure at work affect you more than most people. About 1 in 25 to 1 in 30 people of Northern European ancestry are MZ.
• SZ: moderately low AAT. Lung risk rises mainly with smoking. Ask for a blood AAT level.
• ZZ: alpha-1 antitrypsin deficiency, about 1 in 2,000 to 5,000 people of European ancestry. See a doctor. A blood AAT level and phenotype confirm it, lung and liver checks follow, and augmentation therapy exists for people with lung disease. Never smoke.

Why it matters that it's under-diagnosed

Most people with ZZ are never diagnosed, or are diagnosed years late, often after being told they have ordinary asthma or COPD. Respiratory guidelines recommend testing everyone with COPD, and many adults with unexplained liver disease, for AAT deficiency. A raw file can flag it before any of that.

Limits of a raw file

• Only Z and S are read. Rarer deficiency alleles (null variants, M-malton and others) need a clinical test.
• A chip can miscall. ZZ from a chip needs confirming with a blood AAT level and phenotyping or genotyping.
• Family: if you're ZZ or SZ, your siblings have a meaningful chance of the same type.

healthosx.com/dna

Every finding opens up: what it means, what to do, and the genotype behind it.

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The short version: what is worth acting on, first.

Why this one is worth checking even if you feel fine

Most findings in a raw file are curiosities. This one has a clear path from result to action, which is rare:

• A blood test confirms it. An alpha-1 antitrypsin level, plus phenotyping or genotyping, is a standard test any doctor can order.
• The main intervention is free. Not smoking, and avoiding dust, fumes and vapours at work, matters far more for a Z carrier than for anyone else.
• Treatment exists for people with severe deficiency and lung disease: augmentation therapy with pooled human alpha-1 antitrypsin.
• Family follows. Siblings of someone with ZZ have a one-in-four chance of the same type, and it changes their smoking calculus.

Symptoms that should prompt a test

• Breathlessness or wheeze that started young, or COPD without a heavy smoking history
• Recurrent chest infections, or bronchiectasis with no explanation
• Unexplained liver enzyme abnormalities, adult liver disease, or jaundice in infancy
• A family history of emphysema or liver disease at unusual ages

Respiratory guidelines recommend testing everyone diagnosed with COPD, and many adults with unexplained liver disease. Plenty of people who should have been tested never were, which is why a raw file sometimes finds it first.

FAQ

I'm MZ. Does it matter?

Usually not on its own. It shifts the risk if you smoke or work around dust and fumes, which makes those choices more consequential for you than for most people.

Can a chip get this wrong?

Yes — a chip can miscall any position, and rarer deficiency alleles (null variants, M-malton) aren't on it at all. A ZZ result from a chip needs confirming with a blood level.

Does this affect my children?

Each child inherits one of your two alleles. If you and your partner are both MZ, each child has a one-in-four chance of ZZ. Testing both parents is the way to settle it.

Check your Pi type from the raw file you already have: healthosx.com/dna