Gene variant may help against emphysema, asthma

Uncommon version seems to lessen risk of lung disease in smokers

People who carry a variant form of a gene that encodes a protein called MMP-12 are in luck. This uncommon form of the gene appears to provide some protection against emphysema and asthma, researchers report online December 16 in the New England Journal of Medicine.
In the study, an international team of researchers analyzed data on lung function and genetics from seven studies that included more than 5,000 people and found that 7 to 13 percent of people harbored the beneficial variant of MMP-12.
In four of the studies, the scientists found that tobacco smokers carrying the helpful form of the protein were one-third less likely to develop chronic obstructive pulmonary disease than other smokers. COPD includes emphysema and chronic obstructive bronchitis and is the fourth leading cause of death in the United States after heart disease, cancer and stroke.
In the three other studies, children with asthma who also had the MMP12 variant had substantially milder disease than their asthmatic counterparts without the gene variant. 
The MMPs, short for matrix metalloproteinases, make up a family of proteins with many duties in the body. In the lungs, MMP-12 protein is made by immune cells and has been implicated in emphysema because it can degrade connective tissues such as elastin, which gives lungs elasticity. 
Smoke inhalation brings on rampant inflammation that’s incited by an immune reaction to chemicals in the smoke. This can result in higher than normal MMP-12 production by cells in the lung and excess breakdown of elastin, which in turn may reduce the lungs’ flexibility. 
Making less MMP-12 might be better for people with either disease. For example, past research in mice exposed to cigarette smoke found that animals lacking MMP-12 were protected against emphysema. 
It is widely accepted in the scientific community that asthma and COPD stem from a combination of environmental and genetic factors, says study coauthor Juan Celedón, a pulmonologist at Harvard Medical School and Channing Laboratory in Boston. Irritants in the environment such as allergens and bacterial toxins have been linked to asthma, whereas tobacco smoke is the prime environmental culprit in COPD.
The genes that account for heightened risk of asthma or COPD have been much more difficult to track down, Celedón says. But researchers have been able to implicate two other genes. Particular variants of the ADAM33 and TGF-beta-1 genes place the person carrying them at increased risk of these lung diseases, he says.
Lung inflammation occurs in both smokers and people with asthma, says Peter Paré, a pulmonologist at the University of British Columbia in Vancouver, Canada. But he argues that the asthma link to MMP-12 is weaker “since the loss of lung function in that condition is due to scarring and narrowing of airways,” rather than outright destruction of elastin and collagen in lung tissues.
Even though the new finding shows a potential benefit of the variant, it is probably only one of several reasons why many smokers don’t develop COPD, Celedón says. “My sense is that it’s the interaction of various genes and exposures to environmental factors that leads to increased or decreased risk for a particular individual,” he says. 
The new study may lend support to the “Dutch hypothesis,” in which scientists in the Netherlands have proposed that asthma and COPD “are different manifestations of the same disease,” says Guy Brusselle, a physician at Ghent University Hospital in Belgium. 
Writing in the same NEJM issue, Brusselle describes a worst-case scenario in which a person with a higher-risk version of MMP12 has childhood asthma and then smokes during adulthood. That would compound the danger by adding an environmental risk to an unseen genetic one, he says. 

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