SERPINA1

HIGH

Alpha-1 antitrypsin

Chromosome: 14q32.13

Gene Overview

SERPINA1 encodes alpha-1 antitrypsin (A1AT), a serine protease inhibitor that protects lung tissue from neutrophil elastase. The severe Z allele (Glu342Lys) causes protein misfolding and accumulation in hepatocytes, leading to deficiency in lung and liver disease. A1AT deficiency is a major genetic cause of early-onset emphysema and COPD, particularly in smokers. Normal A1AT inhibits neutrophil elastase; deficiency permits unchecked protease activity and alveolar destruction. Expression is hepatic; protein is secreted into serum and reaches lung via circulation. PiZZ homozygotes have ~10-20% of normal A1AT levels. Cigarette smoke oxidatively inactivates A1AT, exacerbating the protease-antiprotease imbalance.

Molecular Function

  • serine protease inhibition
  • elastase inhibition
  • acute phase response

Protein class: serine protease inhibitor (serpin)

Regulatory Annotation

Promoter activity: Acute-phase responsive; IL-6 and inflammation upregulate expression.

eQTL tissues: liver

Tissue Expression Context

liverTPM range: 800-2500GTEx vv8
lungTPM range: 1-5GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

  • copd— GWAS, strength 0.94
  • asthma— literature, strength 0.38

Exposures

  • tobacco— literature, strength 0.91

Mechanistic Hypotheses

A1AT deficiency allows neutrophil elastase to degrade lung elastin unchecked; tobacco smoke further inactivates A1AT and stimulates neutrophil recruitment, creating a protease-antiprotease imbalance that drives emphysema.

PiZZ smokers develop severe emphysema; augmentation therapy reduces lung density loss.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Stoller JK, Aboussouan LS (2005). Alpha-1-antitrypsin deficiency. Lancet. doi:10.1016/S0140-6736(05)67736-6
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.Stoller JK, et al. (2009). Effect of recombinant alpha1-antitrypsin on pulmonary exacerbations in COPD. Thorax. doi:10.1136/thx.2008.102871