What are the genetic causes of Chronic Obstructive Pulmonary Disease (COPD)?

From the Guidelines

The primary genetic cause of COPD is alpha-1 antitrypsin deficiency (AATD), a rare inherited condition where the body lacks sufficient alpha-1 antitrypsin protein. This condition is characterized by mutations in the SERPINA1 gene, with the most severe form resulting from the Z allele (PiZZ genotype) 1. The lack of alpha-1 antitrypsin protein makes the lungs vulnerable to damage, particularly in smokers, leading to early-onset emphysema and COPD.

Key Points to Consider

• AATD is caused by mutations in the SERPINA1 gene, with the most severe form resulting from the Z allele (PiZZ genotype)
• Testing for AATD should be considered in all patients with COPD, especially those with early onset (under 45 years), minimal smoking history, family history of COPD, or predominantly lower-lobe emphysema
• Treatment includes standard COPD therapies plus augmentation therapy with intravenous alpha-1 antitrypsin (typically 60 mg/kg weekly) for those with severe deficiency and evidence of emphysema
• Beyond AATD, other genetic factors likely contribute to COPD susceptibility, including variations in genes involved in detoxification pathways, inflammatory responses, and tissue repair mechanisms, though these have less clear clinical implications currently 1

Clinical Implications

• Early identification of AATD is crucial for timely intervention and management of COPD
• Genetic counseling and testing should be considered for family members of patients with AATD
• Further research is needed to understand the role of other genetic factors in COPD susceptibility and to develop targeted therapies.

From the Research

Genetic Causes of COPD

• Alpha-1 Antitrypsin (A1AT) deficiency is a common hereditary disorder associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) 2, 3, 4, 5, 6.
• A1AT deficiency occurs in individuals with deleterious genetic mutations on both chromosomes (maternal and paternal) in SERPINA1, the gene encoding the alpha-1 antitrypsin protein 4.
• The clinical manifestations of A1AT deficiency include panacinar emphysema, airway hyperresponsiveness, and bronchiectasis 5.
• High-risk groups, including individuals with COPD, nonresponsive asthma, bronchiectasis of unknown etiology, or unexplained liver disease, should be tested for A1AT deficiency 2, 6.

Diagnosis and Testing

• Genetic testing with DNA sequencing of SERPINA1 gene is recommended as the initial test for individuals with high clinical suspicion for A1AT deficiency 2.
• Initial measurement of serum A1AT levels is recommended for individuals with moderate clinical suspicion of A1AT deficiency, followed by genetic testing with DNA sequencing of SERPINA1 gene if A1AT level is <23 μmol/L (<1.2 g/L) 2.
• First-degree relatives of individuals with A1AT deficiency should be provided genetic counseling and offered testing for A1AT deficiency 2.

Treatment and Management

• A1AT augmentation therapy is recommended for non-smoking or ex-smoking patients with COPD (FEV1 < 80% predicted; associated with emphysema), with documented deficiency genotypes and severely reduced A1AT level (< 11 μmol/L or < 0.57 g/L) in addition to receiving optimal pharmacological and nonpharmacological therapies for COPD 2.
• Individualized pulmonary rehabilitation, exercise, and educational programs can encourage health-enhancing patient behavior and further improve patient quality of life 3.
• Aggressive avoidance of smoking and biomass burning, vaccinations, antibiotics, exercise, good diet, COPD medications, and serial assessment are also important for effective management of AATD and related diseases 6.