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UI Researchers Find Genetic Link Between Smoking, COPD

University of Iowa researchers have found what they believe is the first link between smoking and decreased expression of a new class of noncoding RNAs (microRNAs) in smokers’ immune cells.

"Only 20 percent of smokers get COPD but no one knows why," says Martha Monick, PhD, professor of internal medicine at the University of Iowa Roy J. and Lucille A. Carver College of Medicine. "This discovery identifies changes in a new class of molecules, microRNAs, that might be driving gene expression that ultimately leads to COPD/emphysema and other smoking-related disorders."

Additionally, Monick says the discovery identifies specific smoking altered microRNAs that may provide future therapeutic targets.

The study, which looks at microRNA and gene expression in lung immune cells, was published online recently in the journal PLoS ONE at http://dx.plos.org/10.1371/journal.pone.0044066. Monick is co-senior author with Mary Wilson, MD, UI professor of internal medicine and microbiology. Joel Graff, PhD, a research scientist in Wilson’s laboratory, is primary author, and Thomas Gross, MD, UI associate professor of internal medicine, is a co-author and oversees the clinical aspects of the research.

According to Monick, the new research identifies changes in microRNAs, a new class of gene expression regulators, in cells from smokers’ compared to nonsmokers' lungs. It is the first study to demonstrate significant down-regulation of these small noncoding RNAs (microRNAs) in lung macrophages from smokers. Macrophages are critical components of the innate immune system and changes in these cells are strongly linked to disease development.

In addition, the study links changes in a specific microRNA (miR-452) to increased production of a protein-degrading enzyme called MMP12, long associated with the development of COPD and emphysema. This research, she says, identifies a novel biological mechanism (changes in microRNA expression controlling disease relevant genes) that may be playing an important role in smoking-related diseases.

"We discovered the massive down-regulation of microRNAs with smoking and and are continuing to study the mechanism of that down regulation. We are also working to identify specific microRNAs, like the one we have linked to MMP12, that alter expression of genes involved in smoking-related diseases," Monick says.

"Despite 50 years of accumulating knowledge on the health hazards of smoking, people continue to smoke. Every day approximately 4,000 people under the age of 18 pick up their first cigarette," Monick says. "Research on the mechanism behind smoking-related diseases and identification of markers to identify high risk individuals remains critically important."

Other UI researchers involved in the study are Linda Powers, Anne Dickson, Jongkwang Kim, Anna Reisetter, Ihab Hassan, and Karol Kremens.

This study was supported by several grants from the National Institutes of Health (NIH R01 HL079901 and NIH R21HL109589, NIH R21 AI080801, NIH R01 AI045540), and the Department of Veteran’s Affairs This research also was funded in part by the National Institute for Environmental Health Sciences through the University of Iowa Environmental Health Sciences Research Center, (NIEHS/NIH P30 ES005605). This study was also made possible by Grant Number UL1RR024979 from the National Center for Research Resources (NCRR), a part of the National Institutes of Health (NIH).