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NIH researchers discover DNA sequences related to lung function
BETHESDA, Md.—Treating disease needs to be about tracking down root causes more than just treating symptoms as was the case for so much of medical history, and researchers with the National Institutes of Health (NIH) have made a solid step along that path with a new study involving data from more than 20,000 individuals that has uncovered several DNA sequences linked to impaired pulmonary function and that shine a light on genetic links to lung disease risk.
In this case, in research published online for Nature Genetics on Dec. 13—in an article titled "Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function"—the scientists combined the results of several smaller studies, thus providing insight into the mechanisms that play into people reaching full lung capacity.
The researchers anticipate that the findings may ultimately lead to better understanding of lung function in general, but also shine a more specific light on such diseases as chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States, as well as diseases like asthma and perhaps lung cancer in some patients.
"We have known for a while that genetic factors put some people at risk for lower lung function—a factor in COPD and a risk for early mortality," says Dr. Stephanie London, a senior investigator at the National Institute of Environmental Health Sciences (NIEHS), and a senior author on the paper. "But, we did not know which specific genetic regions were involved. These findings point to specific gene regions."
After submitting the initial draft of the paper, she says, the reviewers asked London and her team to also crunch the numbers after taking out patients with asthma, COPD and the like—essentially removing the people who were most informative because they had the most genetic associations that were relevant to the research. But in the end, London says, that exercise was indeed useful, as it showed that her team's significant findings still had significance, even in the populations with healthier lung function.
"This has given us confidence that what we have found actually does influence lung function across normal and diseased populations," London says.
Impaired lung function is a hallmark of COPD and other lung diseases, but London points out that it is also linked to mortality in many other diseases, such as cardiovascular disease and cancer. Because of this, having an understanding of at least some of the genes involved in lung function is a first step toward defining the relationship between lung function and mortality. This knowledge, in turn, will help in the development of new screening tools, diagnostic tools and therapies to identify, monitor and manage lung diseases.
"Leveraging our investment in collecting these samples has led to new findings and will help focus future research efforts," says Dr. James P. Kiley, director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute (NHLBI).
To conduct the analysis published in Nature Genetics, the researchers used data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. CHARGE is an ongoing study that combines genome-wide association study (GWAS) results from several population-based studies. Pooling data from many studies gives much greater power to find the specific genes involved than looking at any one study alone, the NIH reports. The individual studies included three U.S.-based population studies supported by the NHLBI: the Artherosclerosis Risk in Communities; the Cardiovascular Health Study; and the Framingham Heart Study; and the Rotterdam Study in the Netherlands.
According to London, her team focused on finding genetic commonalities in DNA that lead to some people having lower lung function than others of the same age, gender, race, size and smoking history.
"This is a beautiful example of how modern genomic approaches can unearth valuable new insights from previous research," says Dr. Linda Birnbaum, director of the NIEHS. "It sets us on a course for learning much more about how lung diseases develop and how environmental triggers like smoking and air pollution work in combination with genes."
Another researcher involved with the consortium recently received follow-up funding from the NHLBI to do deep sequencing around the kinds of "top hits" like London and her team found. There is no assurance that that sequencing work will involve the pulmonary hits that London and her colleagues found, but she says she has submitted her study for possible inclusion with that sequencing effort.
It would be a huge boost to her team's work if it was part of that sequencing effort, London notes, because what often isn't picked up in work like hers are the rare genetic variants that have smaller signal strength and don't show up as well. Because, while the more common genetic variants she has found are important leads, it may turn out the true cause of morbidity and mortality in many cases lies more in how those common variants interact with rare variants, she notes.
Additional research going forward that London plans to pursue includes getting a larger data set to find genetic variants with smaller effects than the ones she and her team identified, and to do more studies on gene-environment interactions with pulmonary function and lung disease.