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Gene variant may aid lung function in asthma patients, smokers

Scientists have found a variant gene that may help protect lung function both in children with asthma and in adults who smoke. Smokers with this variant also have reduced risk of developing chronic obstructive pulmonary disease (COPD), the new study shows.

Asthma is one of the most common chronic conditions nationwide, affecting more than 22 million people of all ages. COPD usually affects older adults and is the fourth leading cause of death in the United States. Both conditions are marked by breathing difficulties caused by chronic inflammation of the lungs, but they differ in their triggers and many other features.

Despite their differences, a few studies have suggested that asthma and COPD may share some genetic underpinnings. To take a closer look, an international research team led by Dr. Juan C. Celedon of Brigham and Women's Hospital analyzed data on more than 8,300 children and adults who had participated in 7 different studies that assessed breathing capacity. The research was supported by NIH's National Heart, Lung and Blood Institute (NHLBI).

The scientists first searched for a link between lung function and variations in the gene MMP12, which encodes a protein called matrix metalloproteinase-12. The protein is produced by inflammatory cells called macrophages in the lungs. MMP12 had previously been implicated as an essential contributor to severe lung disease in mice exposed to cigarette smoke. However, its role in human lung disease was unclear.

In the Dec. 31, 2009, issue of the New England Journal of Medicine, the scientists reported that a variant of MMP12 was linked to improved lung function in children with asthma and in current and former smokers. The variant differs from the more common version by a single nucleotide in the gene's "promoter" region. Promoters regulate gene expression, or how active a gene is. This particular variant has been linked to decreased promoter activity and lower expression of the MMP-12 protein.

In one group of nearly 1,500 initially healthy men, about 200 of whom later developed COPD; those with the variant had a 35 percent reduction in the risk of developing COPD. The variant was also associated with a lower risk of COPD in groups of smokers and families at risk for early-onset COPD. Taken together, these findings suggest that the variant form of MMP12 may serve a protective function in at-risk lungs.

"Our results support previous findings for MMP12 in animal models and suggest that genetic variation in MMP12 plays a role in determining the level of lung function in high-risk groups, including children with asthma and adult smokers," says Celedon. Further research is needed to assess whether reduced levels of the MMP-12 protein prove beneficial in asthma or COPD.

--From the National Institute of Health

For further information on this and other health topics, visit the web site of the National Institute of Health at www.nih.gov.

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