Genetics of chronic obstructive pulmonary disease

Area of Science:

• Pulmonary Medicine
• Genetics
• Environmental Health

Background:

• Chronic obstructive pulmonary disease (COPD) exhibits significant variability in development, with severe alpha 1-antitrypsin deficiency (PI Z) being the only established genetic risk factor.
• While PI Z and smoking accelerate COPD, variability persists, suggesting other genetic and environmental factors are involved.
• Heterozygosity for the Z allele (PI MZ) is increasingly linked to COPD risk, and familial aggregation of COPD is reported in non-deficient individuals.

Purpose of the Study:

• To investigate novel genetic determinants of COPD, focusing on severe, early-onset cases.
• To explore the role of familial aggregation and gene-environment interactions in COPD development.
• To identify genomic regions associated with COPD susceptibility through linkage studies.

Main Methods:

• Enrolled 44 severe, early-onset COPD probands (non-PI Z) and 266 relatives.
• Analyzed familial aggregation of COPD and risk factors in first-degree relatives.
• Discussed limitations of candidate gene association studies and proposed family-based controls and linkage studies for COPD genetics.

Main Results:

• A notable female predominance was observed among early-onset COPD probands.
• First-degree relatives of probands showed increased risk for reduced FEV1, chronic bronchitis, and bronchodilator responsiveness, especially if current or ex-smokers.
• Data strongly support a genetic basis for COPD and gene-by-environment interactions.

Conclusions:

• COPD development is influenced by genetic factors beyond severe alpha 1-antitrypsin deficiency.
• Familial aggregation and gene-environment interactions play crucial roles in COPD pathogenesis.
• Future research should employ family-based linkage studies to identify COPD susceptibility genes and overcome limitations of traditional association studies.