Scientists have identified diverse pathways associated with normal lung function, as well as with airflow obstruction and emphysema, by data-mining large-scale genetic information from over 50,000 subjects. In doing so, they also found a candidate gene that could play a role in susceptibility to chronic obstructive pulmonary disease. COPD is one of the most common causes of death worldwide.
The findings from this major, multi-national research collaboration are published in Human Molecular Genetics. The paper, “Integrated Pathway Genomics of Lung Function and Airflow Obstruction” is featured on the cover of the December issue of the journal.
Dr. Sina Gharib, University of Washington associate professor of medicine and director of the Computational Medicine Core at UW Medicine’s Center for Lung Biology, led the project. Several other UW faculty members, including Dr. Bruce Psaty, professor of medicine and of epidemiology and Dr. Susan Heckbert, professor of epidemiology, both from the Cardiovascular Health Research Unit, along with UW scientists Jennifer Brody and Timothy Birkland, were key contributors to this large international study.
Their approach extended beyond standard methods where single geneticmutations are associated with complex human disease. Instead, the researchers investigated whether these minute genetic perturbations, if occurring at many sites within coherent groups of genes or biomolecular pathways, could lead to observable symptoms and clinical conditions.
The state of the lung is most commonly assessed by blowing forcefully into a device called a spirometer. Several spirometric measurements of the volume of exhaled air and lung capacity are inherited traits. In the general population, spirometric test results showing impaired pulmonary function can indicate lung disease and predict future lung ailments and mortality.
The researchers analyzed data from several genome-wide association studies of lung function by using pathway-based computational approaches. Because the study derived its genomic information from so many people, rather than from animal models or a small number of human tissue samples, the findings are broadly relevant to the general population
Their work identified a large repertoire of more than one hundred gene sets associated with spirometric measures of lung function. By grouping functionally similar pathways, the scientists were able to dissect biological processes linked to lung function, such as cell adhesion, movement, proliferation, and signaling, as well as those regulating immunity and development.
The investigators then applied a similar pathway analysis to a large airflow obstruction genome-wide association study and found many similar gene sets and biological processes. They also identified distinctive pathways that included several involved in tissue remodeling. Airway remodeling and destruction is a characteristic finding in chronic obstructive pulmonary disease and emphysema. The researchers validated their integrative genomic approach by experimentally showing that knocking out a candidate gene mapping to the remodeling pathway in mice modulates their susceptibility to emphysema caused by cigarette smoke exposure. The COPD associated gene identified by this approach is matrix metalloproteinase 10, abbreviated MMP10.
While praising the effectiveness of standard genome-wide association studies in discovering many genetic mutations associated with complex traits, Gharib noted, “They neglect a rich repository of genomic data that can provide additional mechanistic insights into human diseases.”
The researchers believe that their proposed integrative approach could be applied to other available genome-wide association studies to dissect disease mechanisms for many complex human disorders.
Source: University of Washington