Serpine2 identified as novel candidate gene for COPD

Related tags Copd Dna microarray

Researchers have identified a serine protease inhibitor as a novel
candidate susceptibility gene for chronic obstructive pulmonary
disease (COPD). The discovery has major implications, especially in
smokers, where the role of the cell protease inhibitor in the lung
was previously unrecognised.

Using a combination of genetic linkage, microarray gene expression and genetic association studies, a Harvard Medical School research team isolated a serine protease inhibitor known as Serpine2.

Thomas Mariani, head of the lab said the gene was "the most promising susceptibility candidate due to its biological relevance, its expression correlation with disease characteristics, and the allelic association in COPD families and replication in non-familial COPD patients."

Serpine2 is of particular interest to scientists due to the pattern of expression and relationship to alpha-1-antitypsin, the only gene proven to modify risk to COPD. Previous research had identified a region on chromosome 2 that is thought to contain a gene conferring susceptibility to COPD.

"We used DNA chips, or gene expression microarrays, to identify genes within this region that were expressed in the lung,"​ said Sorachai Srisuma of the >Brigham & Women's Hospital, Harvard Medical School.

"Subsequently we showed that specific cells in the lungs express Serpine2, and that its expression is altered in individuals with certain clinical characteristics of COPD. Furthermore, specific forms of the gene, termed polymorphisms or SNPs, were more common in people who developed COPD,"​ he said.

He added the data strongly suggested Serpine2 was a gene capable of modifying COPD risk, particularly in response to smoking.

Serpine2 is a major tissue and cell-associated inhibitor of thrombin and plasmin, but not elastase. But no significant study of this protease inhibitor's expression in normal or diseased lungs had been undertaken previously. In an effort to begin to gain insight into the physiological role of Serpine2 in the lung, the team investigated the temporal and spatial expression pattern of the gene in mouse and human lungs.

Analysis of two independent microarray data sets describing normal mouse lung development revealed prominent Serpine2 expression, which was maximal during formation of the airspaces, which is related to lung maturation. Immunostaining was performed to identify the location of Serpine2 within the lung.

"We are also investigating the specific role of Serpine2 mutations in lung function and the risk of developing COPD in humans and genetically modified animals,"​ Srisuma added. "We hope this line of investigation will show how Serpine2 affects the risk of developing COPD and how smoking contributes to this process."

Srisuma said that he would next pursue a project to identify potential biomarkers in COPD patients from New England and also in Thailand. A collaborative study will proceed related to lung development and pathogenesis of COPD and paediatric lung diseases.

About 16 million Americans suffer from COPD, a chronic inflammatory disorder characterized by a gradual loss of lung function. Strongly associated with cigarette smoking, COPD is the only disease among the top 10 causes of death in the US with an increasing rate of newly diagnosed cases. Already the fourth leading cause of death in the US, some believe it could be the leading cause of death worldwide by 2010. So far, there is no cure for COPD, and doctors can only relieve symptoms.

Similar to diseases like cancer and heart diseases, people who smoke (or breathe second-hand smoke) have an increased risk of developing COPD, including emphysema and chronic bronchitis. Certain individuals are more susceptible than others, in that they have an increased risk of developing disease in response to smoking.

For instance, people with a rare form of the protein made by the gene alpha-1-antitrypsin have a high risk of developing COPD if they smoke. Individuals with the common form of this protein have a low risk of developing emphysema, but increase their chances of getting disease if they smoke.

The study, entitled: "Expression of Serine Proteinase Inhibitor E2, a novel candidate COPD susceptibility gene, in the lung was recently presented at the 35th Congress of the International Union of Physiological Sciences​ in San Diego, March 31 - April 5, 2005.

The American Physiological Society (APS)​ has more than 10,000 members and publishes nearly 4,000 articles every year in its 14 peer-reviewed journals.

Related topics Preclinical Research Ingredients

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