Summary

SERPINA1 rs28929474 is the Z allele of alpha-1 antitrypsin — ZZ homozygotes have severe protease inhibitor deficiency causing accelerated lung destruction (especially with smoking) and liver disease from protein accumulation, while MZ carriers have mildly reduced levels and should absolutely avoid smoking.

Genotype spectrum

MM (Wild-type)

Your protease inhibitor system is fully functional. Your lungs are well-protected against neutrophil elastase damage under normal conditions.

MZ (Carrier)

You carry one copy of the Z allele. Your AAT levels are mildly reduced — sufficient for lung protection under normal conditions but with less margin of safety.

ZZ (Homozygous Z — AATD)

This is a clinically significant finding that requires medical follow-up. Severe AAT deficiency is a diagnosable, manageable condition — but only if you know about it.

Practical takeaway

For MM Carriers (Wild-Type)
• No AATD-related concerns. Standard respiratory health: don't smoke, maintain good air quality.
• No carrier implications.
For MZ Carriers

Smoking is your line in the sand:
• Never start smoking. If you currently smoke, cessation is an urgent health priority — you have less protease protection than MM individuals.
• Avoid secondhand smoke exposure as much as practical.
• Occupational awareness: if you work in environments with dust, fumes, or chemical vapours, use respiratory protection diligently. You have less margin of safety.
• Consider serum AAT level testing to know your baseline (~60-70% of normal expected).
• Pulmonary function: if you develop any respiratory symptoms (persistent cough, shortness of breath, wheezing), get spirometry early — don't dismiss as "just a cold."

Carrier awareness:
• If your partner is also of Northern European ancestry, they may carry the Z allele (~3-5% frequency). If both parents are MZ, each child has a 25% chance of being ZZ.
• Consider discussing with a genetic counsellor if family planning is relevant.
For ZZ Carriers (AATD)

Medical referral — this is a diagnosable condition:
• See a pulmonologist for baseline pulmonary function tests (spirometry, lung volumes, diffusion capacity).
• See a hepatologist or gastroenterologist for liver function assessment (ALT, AST, GGT, bilirubin) and liver ultrasound.
• Get serum AAT level confirmed (expected <57 mg/dL / <11 μM).

Lung protection:
• Never smoke. This is the single most impactful health decision for your genotype. ZZ smokers lose 15-20 years of normal lung function compared to ZZ non-smokers.
• If you currently smoke: Immediate cessation. Seek pharmacological smoking cessation support (NRT, varenicline, bupropion). This is genuinely urgent.
• Avoid secondhand smoke, occupational dust/fumes, and air pollution.
• Annual influenza vaccination. Pneumococcal vaccination. Respiratory infections accelerate lung damage in AATD.
• Regular exercise — maintains lung function and overall fitness. Pulmonary rehabilitation if lung function is already reduced.
• AAT augmentation therapy: discuss with your pulmonologist. Weekly IV infusions of purified huma

Evidence detail

What This Gene Does

SERPINA1 encodes alpha-1 antitrypsin (AAT, also called α1-proteinase inhibitor), a serine protease inhibitor (serpin) produced primarily in the liver and secreted into the bloodstream. AAT's main function is to protect the lungs from neutrophil elastase — a powerful protease released by neutrophils during their normal inflammatory response. Without AAT, neutrophil elastase degrades elastin in the alveolar walls of the lungs, causing progressive, irreversible destruction of lung tissue (emphysema).

The Z allele (rs28929474, Glu342Lys) is the most clinically significant SERPINA1 variant. It causes a conformational change in the AAT protein that has two consequences:

1. Reduced secretion: Z-type AAT misfolds in the endoplasmic reticulum of hepatocytes and polymerises (aggregates). Only ~15% of Z-type AAT is secreted into the bloodstream (vs 100% of normal M-type). ZZ homozygotes have AAT levels of ~10-15% of normal — far below the protective threshold of 11 μM (57 mg/dL).

2. Liver accumulation: The misfolded Z-type AAT polymers accumulate within hepatocytes, causing an ER stress response that can lead to hepatitis, cirrhosis, and hepatocellular carcinoma. This is the "gain-of-toxic-function" component — the liver disease is caused by what the protein does INSIDE the cell, not by its absence from the blood.

This entry functions as both a health variant entry AND a carrier entry. MZ heterozygotes are carriers of the Z allele with mildly reduced AAT levels. They typically don't develop clinical AATD but have modestly increased risk of COPD, particularly if they smoke.

Mechanism

The protease-antiprotease balance:

Normal lung maintenance requires a balance between destructive proteases (which break down damaged tissue for remodelling) and protective antiproteases (which prevent excessive tissue destruction). The most important protease-antiprotease pair:
• Neutrophil elastase — a serine protease released from neutrophil granules during the inflammatory response. Extremely potent: it degrades elastin (the protein that gives lungs their elastic recoil), collagen, and proteoglycans.
• Alpha-1 antitrypsin (AAT) — the primary elastase inhibitor in the lower respiratory tract. AAT binds to neutrophil elastase's active site in a 1:1 irreversible complex, permanently inactivating it.

Normal AAT levels (~20-48 μM, 100-200 mg/dL) provide a substantial protective excess over elastase release. The "protective threshold" is ~11 μM (57 mg/dL) — below this, elastase activity begins to exceed AAT inhibitory capacity, and lung tissue destruction outpaces repair.

The Z allele molecular defect:

Glu342 sits at a critical position in the AAT protein's reactive centre loop hinge — the region that inserts into the A-beta-sheet during the conformational change that occurs when AAT inhibits elastase. The Lys342 substitution (Z allele) destabilises this hinge, causing the reactive centre loop of one AAT molecule to insert into the A-sheet of an adjacent AAT molecule (loop-sheet polymerisation). This creates ordered polymers of AAT that cannot be secreted from hepatocytes.

The dual pathology:

1. Lung disease (loss of function): Only ~15% of Z-AAT reaches the bloodstream. Below the protective threshold, neutrophil elastase goes unopposed → progressive elastin destruction → loss of alveolar walls → emphysema (abnormal permanent enlargement of airspaces). Predominantly affects lung bases (unlike smoking-related emphysema which affects apices first).

2. Liver disease (gain of toxic function): Z-AAT polymers accumulate in the hepatocyte endoplasmic reticulum → ER stress → unfolded protein response → hepatocyte injury → inflammation → fibrosis → cirrhosis → hepatocellular carcinoma (in severe cases). This pathology is independent of the lung disease — it's caused by what the protein does inside the cell.

Why smoking is catastrophic in AATD:

Smoking introduces three compound insults:
1. Increases neutrophil recruitment to lungs → mo

SERPINA1 Alpha1

Summary

Genotype spectrum

Practical takeaway

Evidence detail

Sources (10)