rs28929474 — SERPINA1 Z allele (E342K)

The Z Allele — Alpha-1 Antitrypsin's Most Common Deficiency Variant

Alpha-1 antitrypsin (AAT) is the body's primary defense against neutrophil elastase, a powerful enzyme¹¹ powerful enzyme
Neutrophil elastase is released by white blood cells during inflammation and can break down elastin, the protein that gives lung tissue its elasticity that can destroy lung tissue if left unchecked. The Z allele (Glu342Lys) is the most common genetic variant causing severe AAT deficiency, affecting approximately 1 in 2,000 to 3,500 births²² 1 in 2,000 to 3,500 births
The ZZ genotype occurs in about 1:2,000-3,500 newborns in populations of European descent, though most remain undiagnosed. This single amino acid change — glutamic acid to lysine at position 342 — causes the protein to misfold and polymerize inside liver cells, leading to both lung disease (from lack of AAT in circulation) and liver disease (from toxic accumulation in the liver).

The Mechanism

The Z variant creates a structural instability³³ structural instability
The substitution of acidic glutamic acid with basic lysine at position 342 disrupts protein folding, causing AAT molecules to link together (polymerize) in the endoplasmic reticulum of liver cells that prevents normal secretion from liver cells. Instead of being released into the bloodstream, approximately 85% of Z variant AAT gets retained in hepatocytes as large protein polymers. ZZ homozygotes have serum AAT levels at only 10-20% of normal⁴⁴ 10-20% of normal
Normal AAT levels are approximately 20-53 µM (150-350 mg/dL); ZZ individuals typically have <11 µM, while MZ heterozygotes have approximately 60% of normal levels. This dual pathology — loss of function in the lungs and toxic gain of function in the liver — makes the Z allele unique among common genetic disorders.

The molecular consequence is a loss of protease-antiprotease balance in the lungs. Neutrophil elastase, normally kept in check by AAT, breaks down elastin and collagen in alveolar walls⁵⁵ alveolar walls
The tiny air sacs in the lungs where oxygen and carbon dioxide exchange occurs. Without sufficient AAT protection, this leads to panlobular emphysema — progressive destruction of lung tissue starting in the bases and spreading throughout the lungs.

The Evidence

The clinical significance of the Z allele is well established through decades of research. ZZ homozygotes face 80-100% risk of developing emphysema⁶⁶ ZZ homozygotes face 80-100% risk of developing emphysema
Based on ClinGen classification and long-term follow-up studies of diagnosed individuals and 10-15% risk of liver cirrhosis by adulthood. The risk is dramatically modified by environmental factors, particularly smoking⁷⁷ smoking
Smoking increases COPD risk in ZZ individuals and accelerates disease onset by 10-15 years compared to non-smokers.

MZ heterozygotes (carriers) were long considered "safe," but recent large population studies have overturned this assumption. A meta-analysis of six studies⁸⁸ meta-analysis of six studies
Dahl et al., European Respiratory Journal, 2005 found MZ smokers have 3.26-fold increased odds of COPD compared to MM individuals (95% CI: 1.24-8.57). Non-smoking MZ carriers do not appear to have increased lung disease risk, demonstrating a clear gene-environment interaction⁹⁹ gene-environment interaction
The triple combination of MZ genotype, smoking, and occupational dust/fume exposure compounds risk beyond any single factor.

For liver disease, a large cohort study¹⁰¹⁰ large cohort study
Published in Hepatology, 2018 found MZ heterozygotes have 1.53 odds ratio for cirrhosis compared to MM individuals, with risk amplified by higher BMI. Among ZZ children, 18% develop clinically recognized liver abnormalities and 2.4% develop cirrhosis in childhood¹¹¹¹ 2.4% develop cirrhosis in childhood
Swedish newborn screening study following 200,000 children, though most ZZ children remain clinically well.

Practical Implications

The Z allele is one of the most actionable genetic findings in genomics. Smoking avoidance is critical — the difference between a normal lifespan and severe disability by age 40. Augmentation therapy¹²¹² Augmentation therapy
Intravenous infusions of pooled human AAT, administered weekly at 60 mg/kg, raise serum levels into the protective range is available for ZZ individuals with established lung disease, and has been shown to slow emphysema progression in randomized controlled trials¹³¹³ randomized controlled trials
The RAPID trial demonstrated significant reduction in lung density loss: 1.5 g/L/year with treatment vs 2.6 g/L/year with placebo (p=0.07). The therapy is not curative but can meaningfully slow disease progression when started early.

For MZ carriers, counseling about smoking and occupational exposures is essential. Vapors, gases, dusts, and fumes¹⁴¹⁴ Vapors, gases, dusts, and fumes
Agricultural chemicals, welding fumes, silica dust, and other occupational exposures interact with MZ genotype to increase COPD risk common in agriculture, welding, and industrial settings pose added risk. Air pollution and long-term ozone exposure are also independent risk factors for lung impairment in both ZZ and MZ individuals.

Liver monitoring is warranted for all ZZ individuals and should be considered for MZ carriers with other liver disease risk factors. The variable clinical presentation means some ZZ individuals develop life-threatening liver disease in childhood while others remain asymptomatic into adulthood. Genetic counseling and family testing is recommended — first-degree relatives of diagnosed individuals should be offered testing to enable preventive measures.

Interactions

The Z allele interacts significantly with the S allele (rs17580)¹⁵¹⁵ S allele (rs17580)
The S allele (Glu264Val) causes milder AAT deficiency, with serum levels at 60% of normal. SZ compound heterozygotes have AAT levels intermediate between MZ and ZZ, with 20-50% risk of emphysema depending on smoking exposure. The combination warrants similar preventive counseling as for MZ carriers, particularly regarding smoking avoidance.

Beyond SERPINA1, other genes modify lung disease risk in AAT deficiency. Cryptic SERPINA1 haplotypes¹⁶¹⁶ Cryptic SERPINA1 haplotypes
Six haplotypes with a common backbone of five SNPs were found to increase COPD risk 6-50 fold, the highest risk reported for COPD genetics. Variants in SERPINE2 (encoding another protease inhibitor) are associated with emphysema severity in autopsy studies.

The relationship between AAT deficiency and liver disease in other chronic conditions is complex. Z allele carriage increases liver disease risk in cystic fibrosis¹⁷¹⁷ Z allele carriage increases liver disease risk in cystic fibrosis
4.17-fold increased odds of CF-related liver disease and chronic hepatitis C, suggesting that AAT deficiency exacerbates liver injury from other causes. However, hepatocellular carcinoma risk in ZZ cirrhosis is lower (0.88%/year) than in cirrhosis from viral hepatitis or NASH, challenging earlier assumptions about cancer risk.

A compound implication for MZ + active smoking + occupational dust/fume exposure would be warranted given the documented three-way interaction, with recommendations for aggressive exposure reduction and earlier pulmonary function monitoring.