BETHESDA, Md.—Treating disease needs to be about trackingdown root causes more than just treating symptoms as was the case for so muchof 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 frommore than 20,000 individuals that has uncovered several DNA sequences linked toimpaired pulmonary function and that shine a light on genetic links to lungdisease risk.
In this case, in research published online for NatureGenetics on Dec. 13—in an article titled"Meta-analyses of genome-wide association studies identify multiple lociassociated with pulmonary function"—the scientists combined the results ofseveral smaller studies, thus providing insight into the mechanisms that playinto people reaching full lung capacity.
The researchers anticipate that the findings may ultimatelylead to better understanding of lung function in general, but also shine a morespecific light on such diseases as chronic obstructive pulmonary disease(COPD), the fourth leading cause of death in the United States, as well asdiseases like asthma and perhaps lung cancer in some patients.
"We have known for a while that genetic factors put somepeople at risk for lower lung function—a factor in COPD and a risk for earlymortality," says Dr. Stephanie London, a senior investigator at the NationalInstitute of Environmental Health Sciences (NIEHS), and a senior author on thepaper. "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 takingout patients with asthma, COPD and the like—essentially removing the people whowere most informative because they had the most genetic associations that wererelevant to the research. But in the end, London says, that exercise was indeeduseful, as it showed that her team's significant findings still hadsignificance, even in the populations with healthier lung function.
"This has given us confidence that what we have foundactually does influence lung function across normal and diseased populations,"London says.
Impaired lung function is a hallmark of COPD and other lungdiseases, but London points out that it is also linked to mortality in manyother diseases, such as cardiovascular disease and cancer. Because of this,having an understanding of at least some of the genes involved in lung functionis a first step toward defining the relationship between lung function andmortality. This knowledge, in turn, will help in the development of newscreening tools, diagnostic tools and therapies to identify, monitor and managelung diseases.
"Leveraging our investment in collecting these samples hasled to new findings and will help focus future research efforts," says Dr.James P. Kiley, director of the Division of Lung Diseases at the NationalHeart, Lung, and Blood Institute (NHLBI).
To conduct the analysis published in Nature Genetics, the researchers used data from the Cohorts forHeart and Aging Research in Genomic Epidemiology (CHARGE) consortium. CHARGE isan ongoing study that combines genome-wide association study (GWAS) resultsfrom several population-based studies. Pooling data from many studies givesmuch greater power to find the specific genes involved than looking at any onestudy alone, the NIH reports. The individual studies included three U.S.-basedpopulation studies supported by the NHLBI: the Artherosclerosis Risk inCommunities; the Cardiovascular Health Study; and the Framingham Heart Study;and the Rotterdam Study in the Netherlands.
According to London, her team focused on finding geneticcommonalities in DNA that lead to some people having lower lung function thanothers of the same age, gender, race, size and smoking history. "This is a beautiful example of how modern genomicapproaches can unearth valuable new insights from previous research," says Dr.Linda Birnbaum, director of the NIEHS. "It sets us on a course for learningmuch more about how lung diseases develop and how environmental triggers likesmoking and air pollution work in combination with genes."
Another researcher involved with the consortium recentlyreceived follow-up funding from the NHLBI to do deep sequencing around thekinds of "top hits" like London and her team found. There is no assurance thatthat sequencing work will involve the pulmonary hits that London and her colleaguesfound, but she says she has submitted her study for possible inclusion withthat sequencing effort.
It would be a huge boost to her team's work if it was partof that sequencing effort, London notes, because what often isn't picked up inwork like hers are the rare genetic variants that have smaller signal strengthand don't show up as well. Because, while the more common genetic variants shehas found are important leads, it may turn out the true cause of morbidity andmortality in many cases lies more in how those common variants interact withrare variants, she notes.
Additional research going forward that London plans topursue includes getting a larger data set to find genetic variants with smallereffects than the ones she and her team identified, and to do more studies ongene-environment interactions with pulmonary function and lung disease.
