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Chronic Obstructive Pulmonary Disorders Improving Diagnosis and Treatment Using Genotyping HPCGG Helix Newsletter, June 2004
Chronic obstructive pulmonary disorders (COPD), which includes chronic bronchitis and emphysema, are the fourth leading cause of death in the United States, and much of the world. Striking those in their sixties and older, these diseases destroy the tissues of the lung, leaving those affected with mild to severe respiratory problems. Progressive in nature, with no known cure, COPD often proves fatal. Improving diagnosis and treatment of both asthma and COPD is a top priority for Scott Weiss, M.D., Professor of Medicine at Brigham and Women's Hospital and Program Director for Pulmonary Diseases for the Harvard-Partners Center for Genetics and Genomics (HPCGG). In 1996 Weiss became Director of the Respiratory, Genetic, and Environmental Research Group at Brigham's Channing Laboratory. Since then he has grown the group from four faculty and 20 staff, to one with 30 faculty and over 100 staff and support, turning the Channing Laboratory into the world leader in the study of the genetics and epidemiology of COPD and asthma. "Childhood asthma and COPD are inexorably linked," said Weiss. This association is of major public concern given that the prevalence of asthma, itself rarely fatal, has increased in the US by 80 percent since the late 1980s, according to the Centers for Disease Control. Weiss' lab studies the epidemiology, genetics and pharmacogenetics of both diseases. His group were first to link in utero cigarette smoke, allergen exposure, stress and obesity to the development of asthma. "One of our major focuses right now is on gene finding," said Weiss. Recently, his group identified genetic variations that predispose carriers to asthma. They found polymorphisms in both the promoter and 3' untranslated region of the interleukin 10 gene, and a single nucleotide polymorphism in the promoter for the TGF beta gene, which are associated with increased asthma severity. For the latter, a case control study of almost 700 volunteers showed that a single transition from cytosine to thymine almost triples the likelihood that the carrier will be asthmatic. Such studies of complex genetic traits demand the integration of many different disciplines. "We need to have robust bioinformatics and statistical capabilities, well-defined population resources and state-of-the-art technology for doing sequencing and genotyping," Weiss explained. Much of his work is done with the direct support of the HPCGG. "The genotyping facility that we run is something that David Kwiatkowski, M.D., Ph.D. and I developed with Raju Kucherlapati, and it has been integral to our research," Weiss emphasized. Kwiatkowski is associate professor of medicine at Brigham and Women's Hospital. Currently the lab is producing over 1 million genotypes a year with a 99% completion rate and a less than 1% discordancy. Weiss believes that genotyping will help researchers find new ways to treat and diagnose COPD and asthma. "Treatment for asthma has hardly changed in the last 20 years," he remarked. The two drugs of choice are still corticosteroids and beta2 adrenergic receptor blockers, which relieve symptoms by dilating air passages and increasing airway responsiveness. "The trouble with inhaled corticosteroids and beta2 agonists," said Weiss, "is that a substantial fraction of the population are unresponsive to a given drug." Understanding which patients respond to treatment, and why, would be of enormous benefit to doctors, patients, and a medical system that is straining to cut costs and improve efficiency. Weiss' group already has some answers. In a paper hot off the press, he describes polymorphisms that predict response to inhaled corticosteroids. These genetic variations lie in a gene that codes for corticotropin releasing factor receptor 1 (CRFR1), a protein that plays a primary role in regulation release of adrenocorticotropic hormone (ACTH) from the pituitary. Because ACTH regulates release of corticosteroids from the adrenal glands, CRFR1 plays a pivotal roles in regulating circulating steroid levels. Weiss' lab found single nucleotide polymorphisms within the CRFR1 gene that were associated with a twenty to thirty percent increase in lung capacity in response to inhaled corticosteroids. Similarly, last year his group identified genetic variations in the beta2 adrenergic receptor that are associated with increased spirometry, or breathing capacity, and bronchodilator responsiveness to beta2 agonists. These two findings alone will be of enormous benefit to doctors trying to identify who may be at risk for asthma and which drugs to administer when the need arises. To aid with diagnosis Weiss is developing a DNA based diagnostic test that can be used to predict steroid treatment response by genotyping of asthmatics. Pharmacogenomics will also be enormously beneficial for COPD sufferers as well. While COPD causes irreversible damage to the respiratory tissues, it also has a reversible component that is linked to inflammation, and like asthmatics, those with COPD can have periodic "attacks," which can range from episodes of shortness of breath to extreme respiratory distress. More important for COPD, perhaps, given its higher morbidity and mortality, is the ability to prevent onset. With this in mind, Dr. Edwin Silverman in Weiss's lab has embarked on a mission to find polymorphisms that predispose individuals to these devastating diseases, and that will identify genes that play crucial roles in maintenance or destruction of lung tissue. His work has already identified candidate genes and has gathered data from affected populations, most notably extended families that suffer from early-onset COPD. The incidence of asthma and COPD is on the rise worldwide. Fortunately, so is the number of known genetic associations. Over the next year or so Weiss expects that between his and abs, four to six new asthma or COPD genes will be revealed. And he expects the numbers to grow exponentially. The key then, he suggests, is to find out how all those genetic variants interact with each other and with environmental factors, such as tobacco smoke and allergens, and to use that information to develop therapeutics that can stop or halt the pathological process. |