Association studies of lung function in mice

Area of Science:

• Genetics
• Pulmonary Medicine
• Physiology

Background:

• Chronic obstructive pulmonary disease (COPD) is a leading cause of death, characterized by declining lung function.
• Identifying genetic factors influencing lung function is essential for understanding COPD susceptibility.
• Previous genome-wide linkage analysis identified Quantitative Trait Loci (QTLs) associated with lung function in mice.

Purpose of the Study:

• To identify genetic loci and candidate genes contributing to variations in lung function.
• To investigate the role of specific genes, such as SOD3, in regulating lung physiology.
• To explore the translational potential of mouse genetic findings for human lung diseases.

Main Methods:

• Genome-wide linkage analysis in inbred mice with divergent lung function.
• Expression QTL (e-QTL) mapping and exon-wise sequencing of candidate genes.
• Functional validation using gene-targeted Sod3 knockout mice.

Main Results:

• Multiple QTLs for lung function traits (TLC, VD, C(L), D(co)) were identified on mouse chromosomes 5, 15, 17, and 19.
• Four candidate genes were proposed: SOD3, TFF2, ENPP2, and RLN1, located on chromosomes linked to specific lung function parameters.
• Sod3 knockout mice exhibited increased conducting airway volume, supporting SOD3's role in V(D)/TLC.

Conclusions:

• SOD3 is a contributing genetic factor for the complex trait of conducting airway volume.
• The identified mouse QTLs and candidate genes provide insights into the genetic architecture of lung function.
• Further investigation of human variations in these genes is warranted for translational applications in lung development and disease.