SERPINE2 identified as novel candidate gene for COPD, especially with smoking

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."


*Paper presentation: "Expression of Serine Proteinase Inhibitor E2, a novel candidate COPD susceptibility gene, in the lung,"
12:30 p.m.-3 p.m. Tuesday April 5, Physiology 936.4/board #A490. On view 7:30 a.m. - 4 p.m.


Feature topic presentation: Srisuma also is participating in featured topic session #477, "Receptors and signaling pathways
in lung injury and repair," Sunday April 3 room 30A. It begins at 3:15 p.m. Srisuma's presentation is scheduled for 4:15 p.m.



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.















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.


SERPINE2 shows analogous pattern in diseased human, normal mouse lungs


Prominent immunolocalization of SERPINE2 was observed in a cell-associated pattern within bronchiolar airway epithelial cells
and in an extracellular matrix-associated pattern in the vascular adventitia. Immunohistochemistry in human lungs
demonstrated an analogous staining pattern. "Our studies revealed cell-specific and developmentally-regulated expression of
SERPINE2 in the lung, which supports further investigation of this gene's role in human lung diseases," Srisuma said.



Next steps. Already the group has characterized where and when SERPINE2 is expressed in the lung at various developmental
stages. "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 noted. "We hope this line of investigation will show how SERPINE2
affects the risk of developing COPD and how smoking contributes to this process," he added.


In the future, Srisuma will pursue a project identifying potential biomarkers in COPD patients from New England and also in
his native Thailand. When he completes his current post-doctoral fellowship and returns home, a collaborative study will
proceed related to lung development and pathogenesis of COPD and pediatric lung diseases.


Funding. This and related research are supported by the National Institutes of Health.


Scope of the problem, hope for behavior change


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 U.S.
with an increasing rate of newly diagnosed cases. Already the fourth leading cause of death in the U.S., 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.



Srisuma said that nearly all individuals are thought to have other genes that contribute to their risk of developing COPD.
Researchers have previously identified some candidate susceptibility genes and further studies may help identify people with
increased risk of disease. "The identification of individuals with increased risk would be beneficial," he said, "if they can
modify their smoking behavior. Further research also may hasten the detection diseased individuals, which will be especially
useful if it also leads to potential therapies," Srisuma added.


The 35th IUPS Congress (iups2005) is organized by the six member
societies of the U.S. National Committee of the IUPS, the American Physiological Society, the Society for Neuroscience, the
Microcirculatory Society, the Society of General Physiologists, the Biomedical Engineering Society, and the Society for
Integrative and Comparative Biology, under the auspices of the U.S. National Academy of Sciences.


The IUPS conference, held every four years, runs concurrently this year with Experimental Biology 2005 at the San Diego
Convention Center.


The American Physiological Society (APS), which is hosting IUPS, was founded in 1887 to foster basic and applied science,
much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes nearly 4,000
articles every year in its 14 peer-reviewed journals. In May, APS received the Presidential Award for Excellence in Science,
Mathematics and Engineering Mentoring (PAESMEM).


Editor's Note: For further information or to schedule an interview with a member of the research team, please contact Mayer
Resnick at the IUPS/APS newsroom 619-525-6228 (March 31-April 6), or 301-332-4402 (cell) or 301-634-7209 (office), or Stacy
Brooks at 240-432-9697 (cell) or 301-634-7253 (office).


A searchable online program for IUPS and EB is at faseb/meetings/eb2005/call/default.htm


Contact: Mayer Resnick

mresnickthe-aps

301-332-4402 (cell)

301-634-7209 (office, outside IUPS dates)

American Physiological Society

the-aps


IUPS/APS Newsroom March 29-April 6

San Diego Convention Center

Hall E Registration Area/Flex Unit

Telephone: 619-525-6228