Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Area of Science:

• Genetics
• Pulmonology
• Environmental Health

Background:

• Genome-wide association studies (GWAS) have identified common genetic variants linked to lung function.
• Rare and low-frequency genetic variants, particularly their interaction with environmental factors like smoking, remain underexplored.
• Cigarette smoking is a primary environmental risk factor for diminished lung function.

Purpose of the Study:

• To investigate gene-by-smoking interactions for rare and low-frequency exonic variants influencing pulmonary function.
• To identify novel genetic associations with lung function, considering the impact of smoking.
• To assess the combined effects of genetic predisposition and smoking on lung function measures.

Main Methods:

• A large-scale gene-smoking interaction meta-analysis was performed on exonic rare and low-frequency variants.
• Discovery stage involved 44,429 individuals of European ancestry.
• Replication was sought in the UK BiLEVE (45,133 samples) and UK Biobank (59,478 samples) studies.
• Both gene-by-smoking interaction effects and joint genetic and interaction effects were tested.

Main Results:

• A previously reported low-frequency signal in GPR126 replicated, distinct from common variant associations.
• A top rare variant signal (rs142935352) showed nominal replication in one study.
• Interaction and joint tests revealed significant associations between current smoking, PDE3B variants, and forced expiratory volume in one second (FEV1).

Conclusions:

• Gene-by-smoking interactions play a significant role in determining pulmonary function.
• The study highlights the importance of investigating rare variants and their environmental interactions for a comprehensive understanding of lung function.
• PDE3B gene variants interacting with smoking are associated with reduced FEV1, underscoring their clinical relevance.