TORONTO (May 22, 2011) – In an age where personalized medicine is within reach, a one-size-fits-all approach just won’t cut it. A group of North American researchers have identified two “modifier” genes in the genomes of cystic fibrosis patients that may be responsible for variation in severity between patients. This is the first study to show evidence that modifier genes affect lung disease severity in cystic fibrosis.
The scientists set out to find out why some cystic fibrosis patients had a good quality of life, while others who carried the same mistakes in their cystic fibrosis genes were experiencing severe lung disease, were in need of lung transplants, or died. Their discovery of modifying genes may eventually lead to tailoring treatment to patients according to their individual disease. The study is reported in the May 22 advance online edition of Nature Genetics.
Nearly a decade ago, the Canadian team, led by Dr. Peter Durie at The Hospital for Sick Children (SickKids) teamed up with researchers and 37 cystic fibrosis clinics across the country and obtained DNA and information about the lungs, intestine, liver and pancreas of 75 per cent of the Canadian cystic fibrosis population. After discovering that their colleagues at the Johns Hopkins University School of Medicine and the University of North Carolina at Chapel Hill were doing similar studies, the three teams decided to form the North American Cystic Fibrosis Gene Modifier Consortium and joined forces with other centres across the continent in a genome-wide association study involving more than 3,400 patients.
“We discovered that people with cystic fibrosis didn’t necessarily show predictable disease progression patterns,” says Durie, Staff Gastroenterologist and Senior Scientist at SickKids and a lead investigator of the Canadian Consortium for Cystic Fibrosis Genetic Studies. “If you look at the lung function of patients, even those that inherited identical mutations in the cystic fibrosis gene, disease severity and lung function decline can differ substantially. We know that these patients all have cystic fibrosis, but the rate at which their lungs are deteriorating is variable.”
Back in 1989, SickKids scientists discovered the cystic fibrosis transmembrane conductance regulator (CFTR) – the gene that causes the disease. In cystic fibrosis, two copies of the abnormal and established causal gene must be present for the disease to develop. In the new study, researchers were able to identify regions on chromosomes 11 and 20 that influence the severity of lung disease and its progression.
Durie notes this is a major step toward therapeutic targets for patients with cystic fibrosis and other diseases. “This is a paradigm shift in how to approach treating a disease. Historically, we have treated the consequences of the disease – the symptoms and secondary infections that develop – but we are now looking at treating the basic contributors to the disease at a genetic level. If we understand what the genes are, we can find ways to tweak the genes or the protein products using drugs.”
Dr. Lisa Strug, another SickKids team member, notes that “while advances have come from knowing the causal cystic fibrosis gene, all the genes that affect progression of disease also need to be identified. Members of the Consortium are continuing to achieve this goal.”
This work was achieved by a strong collaborative effort by members of the Canadian Consortium for Cystic Fibrosis Genetic Studies research, which includes Drs. Mary Corey, Ruslan Dorfman and Julian Zielenski at SickKids, Lei Sun at the University of Toronto, Yves Berthiaume at the University of Montreal and Peter Paré and Andrew Sandford at the University of British Columbia.
In some Canadian provinces, cystic fibrosis is being diagnosed by newborn screening, so patients can be monitored even before they show the first signs of lung disease. The ultimate goal is to be able to predict the severity of cystic fibrosis disease of each individual before they get symptoms and to tailor their treatment based upon knowledge of their genetic makeup, thus preventing progression of the disease.
“We know that cystic fibrosis affects each individual differently,” says Maureen Adamson, CEO, Cystic Fibrosis Canada. “This research helps us understand why some cases of cystic fibrosis are more severe. Cystic Fibrosis Canada is pleased to partner in this study which may help tailor treatments to individual patients and improve health outcomes.”
“We are proud to have played a part in what is the first ever study of its kind looking into the genetic variations of the most severe forms of cystic fibrosis,” comments Dr. Mark Poznansky, President and CEO of the Ontario Genomics Institute. “This work will eventually allow for more accurate and timely prediction of how this most debilitating disease develops, and will greatly assist in the choice of treatment. This research also acts as a superb example of how collaboration between leading institutions across Canada and the US can really pay off and produce significant findings that have the potential to change the landscape in treatment for cystic fibrosis.”
Cystic fibrosis is one of the most common inherited chronic lung diseases, affecting one in every 3,600 children born in Canada. It is characterized by a build-up of mucus in the lungs and in the ducts of the pancreas, causing breathing and digestion problems.
Durie is also Professor in the Department of Paediatrics and Member of the Institute of Medical Science at the University of Toronto.
The study was supported through the National Institutes of Health, Cystic Fibrosis Foundation, Flight Attendant Medical Research Institute, Lawson Wilkins Pediatric Endocrine Society, Cystic Fibrosis Canada, Genome Canada through the Ontario Genomics Institute, Ontario Research Fund – Research Excellence Program, Lloyd Carr-Harris Foundation, Joint Fellowship of Canadian Institutes of Health Research and Ontario Women’s Health Council, andSickKids Foundation.
About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca.
About SickKids Research & Learning Tower
SickKids Research & Learning Tower will bring together researchers from different scientific disciplines and a variety of clinical perspectives, to accelerate discoveries, new knowledge and their application to child health — a different concept from traditional research building designs. TheTower will physically connect SickKids science, discovery and learning activities to its clinical operations. Designed by award-winning architects Diamond + Schmitt Inc. and HDR Inc. with a goal to achieve LEED® Gold Certification for sustainable design, the Tower will create an architectural landmark as the eastern gateway to Toronto’s Discovery District. SickKids Research & Learning Tower is funded by a grant from the Canada Foundation for Innovation and community support for the ongoing fundraising campaign. For more information, please visit www.buildsickkids.com.
About Cystic Fibrosis Canada
Cystic Fibrosis Canada is a national health charity committed to finding a cure for cystic fibrosis, and to helping people and families affected by cystic fibrosis cope with their daily fight. As a global leader in CF research, the organization invests more dollars in life-saving cystic fibrosis research and care than any other non-government agency in Canada. In 2011, Cystic Fibrosis Canada is investing nearly $6.5 million to fund 56 promising research projects, as well as more than 50 fellows and students, and is delivering more than $2 million to fund clinical care programs in Canada.
For more information, please contact:
The Hospital for Sick Children
416-813-7654, ext. 2059
Cystic Fibrosis Canada
1-800-378-2233, ext. 290