Integrative Genomics of Emphysema-Associated Genes Reveals Potential Disease Biomarkers

RATIONALE: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Gene expression profiling across multiple regions of the same lung identified genes significantly related to emphysema.

OBJECTIVE: To determine whether the lung and epithelial expression of 127 emphysema-related genes is also related to lung function in independent cohorts and whether any of these genes could be used as biomarkers in the peripheral blood of COPD patients.

METHODS: We determined whether the expression levels of the 127 emphysema genes were under genetic control in lung tissue (n=1,111). We then determined whether the mRNA levels of these genes in lung tissue (n=727), small airway epithelial cells (n=238) and peripheral blood (n=620) were significantly related to lung function measurements.

MEASUREMENTS AND MAIN RESULTS: The expression 63 of the 127 (50%) genes was under genetic control in lung tissue. The lung and epithelial mRNA expression of a subset of the emphysema-associated genes, including ASRGL1, LPHN2, and EDNRB, were strongly associated with lung function. In peripheral blood, the expression of 40 genes was significantly associated with lung function; of which 29 (73%) genes were also associated with lung function in lung tissue yet with opposite direction of effect for 24 of the 29 genes including those involved in hypoxia and B cell related responses.

CONCLUSION: Integrative genomics uncovered a significant overlap of emphysema genes associations with lung function between lung and blood with opposite directions between the two. The results support the use of peripheral blood to detect disease biomarkers.