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October 5, 2005

Study proves genetic variations influence severity of cystic fibrosis

TORONTO - Subtle differences in genes other than the defective CFTR (cystic fibrosis transmembrane conductance regulator) gene known to cause the disease cystic fibrosis (CF), can significantly modify the severity of CF, a large new multi-centre international study has concluded. A report on the findings appears in the October 6 issue of The New England Journal of Medicine.

The study, led by University of North Carolina (UNC) at Chapel Hill , Case Western University and The Hospital for Sick Children (SickKids), shows for the first time that particular variants of the transforming growth factor beta 1 (TGF b 1) gene are largely responsible for how badly the illness affects patients' lungs.

More than 50 hospitals and medical centres and scores of physicians across Canada and the United States participated in the investigation, which was actually two closely related studies with separate groups of patients. Findings were essentially the same for both groups, but the large pool of subjects was needed to make the data statistically significant.

“This is a very important study in terms of understanding molecular mechanisms of CF as well as its potential for disease prognosis and treatment,” said Dr. Julian Zielenski, project director in Genetics & Genomic Biology at SickKids and co-author of the paper “Although, mutations in the CFTR gene are the primary cause of CF, variations in other genes, called CF modifiers, may significantly affect the severity of CF.”

Due to the complex interactions between modifier genes and the environment, a modifier gene study requires a large study population in order to be conclusive.

“We are confident in this study's findings, specifically of the adverse effect of the TGF b 1 gene on the severity of lung disease in CF, as this was the first truly large-scale, well-designed study satisfying all criteria required to draw meaningful conclusions,” said Dr. Zielenski.

“We are very grateful for the enthusiastic participation of persons with CF and their families as well as the CF Clinics across Canada, as we would not be able to conduct this research without them,” added Dr. Zielenski. “We will continue to collaborate with the US groups to study more modifier genes for CF, as well the role of these modifier genes in other diseases such as chronic obstructive pulmonary disease.”

According to principal investigator Dr. Michael R. Knowles, professor of medicine at the UNC School of Medicine, this study is especially important in the field of genetic modifiers, because there were enough patients -- over 1,300 -- and a robust study design to assure that their observations are likely correct. “That is in contrast to much of the previous work in this area where the number of subjects was usually too small to be conclusive,” said Dr. Knowles.

The size of the study enabled the researchers to take into account numerous possible variables such as sex, other illnesses like asthma, enrollment sites, associated diseases and infections.

“The observation has tremendous implications about the future for prognosis and potential new therapies in CF,” Dr. Knowles said. “We are on the verge in the next two or three years of being able to test for other such genetic variants across the entire human genome. Our hope is to be able to identify most of the important gene modifiers in CF so that they can be used for prognosis, the identification of novel therapeutic targets and perhaps even directing therapy in an individual patients toward different types of adverse gene modifiers.”

Initially, the study involved 808 cystic fibrosis patients who had inherited an altered form of a gene known as delta F508, the most common CFTR mutation, from both parents. The second study involved 498 people with the condition. By measuring the volume of air when patients' exhaled strongly into a machine, researchers determined how severe each subject's lung disease was.

Scientists then correlated patients' level of illness against various genetic mutations and found that variants of a gene known as TGF b 1 were associated with a more severe case of the disease.

“As this gene is one of about 30,000 genes in our bodies, its identification as a modifier of the CF lung disease allows us a specific target to focus on for improving CF therapy,” said Dr. Mitchell L. Drumm, the study's lead author, associate professor of pediatrics and genetics at Case Western University. “As we better understand its function in lung disease, we hope it will allow us to design better and more specific therapies. Because other researchers have found a similar effect of this gene in asthma, the implications likely extend to other disorders affecting the lungs as well.”

Along with Drs. Zielenski, Drumm and Knowles, 19 authors are listed on the report, comprising an international team of clinicians, scientists and biostatisticians. Other authors on the paper from SickKids are Dr. Peter Durie, senior scientist in Integrative Biology and professor of Paediatrics at the University of Toronto (U of T), Dr. Mary Corey, senior scientist in Population Health Sciences and professor of Public Health Sciences & Paediatrics at U of T, and Dr. Ruslan Dorfman, a postdoctoral fellow in Dr. Zielenski's lab.

SickKids has a long history of CF research that culminated in 1989 with the discovery of the gene responsible for cystic fibrosis (CFTR) by research teams led by Dr. Lap-Chee Tsui. It helped to establish in SickKids a strong interdisciplinary CF Research Program directed by Dr. Peter Durie and supported by the Canadian Cystic Fibrosis Foundation.

This research was supported by Genome Canada through the Ontario Genomics Institute, the Canadian Cystic Fibrosis Foundation, the Cystic Fibrosis Foundation, the National Institutes of Health, the Lloyd Carr Harris Foundation and SickKids Foundation.

The Hospital for Sick Children, affiliated with the University of Toronto , is Canada 's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centered, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca .

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