Using a combination of genetic linkage, microarray gene expression and genetic association studies, a group of Brigham and Women’s Hospital/ Harvard Medical School researchers have identified a serine protease inhibitor clade E, member 2, or SERPINE2, “as a novel candidate susceptibility gene for COPD,” according to Sorachai Srisuma, who is presenting the research at the 35th Congress of the International Union of Physiological Sciences in San Diego, March 31 - April 5, 2005.
The collaborative, multi-disciplinary team includes: Sorachai Srisuma, Dawn L. DeMeo, Brigham H. Mecham, Edwin K. Silverman, Scott T. Weiss, Kathleen J. Haley, John J. Reilly, Steven D. Shapiro, and Thomas J. Mariani. Mariani, head of the lab where Srisuma works, said the gene is “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.”
First major study to seek SERPINE2’s physiological role in lung
Srisuma said SERPINE2 “was of particular interest due to its pattern of expression and relationship to alpha-1-antitypsin, the only gene proven to modify risk to COPD (chronic obstructive pulmonary disease). Our team of human genetic epidemiologists, led by Dawn DeMeo and Edwin Silverman, previously identified a region on chromosome 2 they thought might 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,” Srisuma noted. “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. Taken together, “these data strongly suggest SERPINE2 is a gene capable of modifying COPD risk, particularly in response to smoking,” he added.
SERPINE2 is a major tissue and cell-associated inhibitor of thrombin and plasmin, but not elastase, Srisuma noted. 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, we investigated the temporal and spatial expression pattern of the gene in mouse and human lungs,” he said.