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About SickKids

February 21, 2008

Scientists discover a genetic combination that may worsen pulmonary disease in paediatric CF patients; Finding could pave the way for future clinical trials and genetic tests

TORONTO – Scientists at The Hospital for Sick Children (SickKids), the University of British Columbia (UBC), the University of Toronto (UofT) and Université de Montréal (UdeM) have identified key genetic factors influencing the severity of lung disease in paediatric cystic fibrosis (CF) patients. Their research is reported this month in The Journal of Clinical Investigation .

According to the research, paediatric patients with cystic fibrosis (CF) who carry a gene variant that produces a low amount of MBL2 or mannose binding lectin 2, and who carry a high producing variant of the TGFB1gene or transforming growth factor beta 1 gene, have a greater risk of acquiring the bacterial infection that may accelerate the decline of their lung function.

Virtually all CF patients are prone to acquiring the Pseudomonas aeruginosa bacteria, which leads to the development of lung diseases that progress with age. Because MBL2 plays a key role in the first defense against bacterial infection, the bacteria tend to invade lungs at an earlier age in those who are MBL2 deficient and may lead to a chronic infection and resistance to antibiotics much sooner than in those with normal levels of the protein in their blood. The mechanisms by which elevated levels of TGFB1 lead to more severe lung disease are yet to be investigated.

“The study shows that those exhibiting this genetic combination may be at a higher risk of acquiring this infection at a younger age - on average nearly five years earlier than those with gene variants that produce normal MBL2 and TGFB1 levels - most likely leading to a faster rate of decline of pulmonary function,” explains Dr. Julian Zielenski, an Associate Scientist in the Genetics & Genome Biology program at SickKids and a lead author of the study. “Patients experience a vicious cycle of infection and inflammation that destroys lung tissue, inhibits lung function, and erodes quality of life. Since pulmonary disease is also the leading cause of mortality among CF patients, examining the genetics that help invite, sustain, or advance infection is critical.”

“While we are excited by the discovery and its future implications for prognosis and therapeutics, the findings cannot be used yet to accurately or consistently predict the outcome in individual patients who exhibit this adverse genetic combination,” cautions Zielenski. “There are many other CF modifier genes which may positively or negatively affect CF disease. After a sufficient number are identified, scientists could develop a genetic test to reliably predict the severity of lung disease at the individual level, or begin clinical trials to evaluate the benefit of supplementing these patients with functional MBL2 protein.”

The results for this discovery were derived from a genetic association study that compared the MBL2 and TGFB1genotypes of 1,019 CF children, recruited from Canada 's 37 CF clinics. The study was conducted under the auspices of the Canadian Consortium for CF Genetic Studies, consisting of investigators and clinical collaborators who established a Canadian CF population resource of clinical data and biological material. The Consortium promotes scientific discovery toward a better understanding of CF and related diseases.

Researchers from four Canadian Institutions were involved in the study, whose other key authors include Postdoctoral Fellow in the Genetics & Genome Biology program Dr. Ruslan Dorfman (first author), Senior Scientist in the Physiology & Experimental Medicine program Dr. Peter Durie (co-leader of the Canadian CF Modifier Study), and Senior Scientist in the Child Health Evaluative Sciences program Dr. Mary Corey, all at SickKids, as well as UBC Scientists Drs. Peter Pare and Andrew Sandford, Dr. Lap-Chee Tsui at University of Hong Kong, Dr. Lei Sun, a Biostatistician at UofT, and Dr. Yves Berthiaume, a Clinical Scientist at UdeM. Funding from Genome Canada , with co-funding from the Canadian Cystic Fibrosis Foundation, the Ontario Research Fund –Research Excellence Program, the Lloyd Carr-Harris Foundation, and SickKids Foundation supported the research.

Moving forward, the Canadian Consortium for CF Genetic Studies will search for other CF modifiers using a new approach called a Genome-Wide Association Study. The team at SickKids has partnered with US researchers at the University of North Carolina , Case Western Reserve University , and Johns Hopkins University to study over 5,000 patients, examining 550,000 genetic markers representing the entire human genome. The study is supported by a large grant from the US Cystic Fibrosis Foundation, as well as the US National Institutes of Health, Genome Canada and its co-funders. Using this approach, the team hopes to isolate additional undiscovered genetic modifiers that are not typically associated with CF.

The Hospital for Sick Children (SickKids), 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. As innovators in child health, SickKids improves the health of children by integrating care, research and teaching. Our mission is to provide the best in complex and specialized care by creating scientific and clinical advancements, sharing our knowledge and expertise and championing the development of an accessible, comprehensive and sustainable child health system. For more information, please visit http://www.sickkids.ca/ . SickKids is committed to healthier children for a better world.

For more information, please contact:

Janice Nicholson
Public Affairs
The Hospital for Sick Children
Phone: 416-813-6684
Fax: 416-813-5328
email: janice.nicholson@sickkids.ca