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August 2, 2011

Largest Canadian IBD study uncovers gene associated with ulcerative colitis

TORONTO – For as long as seven-year-old Jonathan Wexler can remember, he has taken sweet orange medicine every day to manage his ulcerative colitis symptoms. When he was only eight months old, Jonathan became the youngest patient to be diagnosed with ulcerative colitis, a form of inflammatory bowel disease (IBD), at The Hospital for Sick Children (SickKids).

In a new study led by SickKids, researchers identified a gene that may play an important role in the development of ulcerative colitis. The results strongly implicate the RAC1 gene as a potential target for new therapies.

Over the past decade, the number of children living with inflammatory bowel disease (IBD) in Ontario has increased by 30 per cent, mostly due to the increased diagnosis of kids under 10 years old. IBD is thought to be caused by a combination of genetics and an immune response to bacteria in the gut, but the exact cause remains unknown.

This study, published in the August 1 edition of Gastroenterology, is the largest Canadian study of its kind. It included over 3,000 participants from Toronto, the United States and Scotland. The average age of participants was 16. The study was first conducted in a local discovery cohort and found that increased RAC1 gene expression was associated with susceptibility to ulcerative colitis. Scientists took this discovery to the next step and tested this association in animal models. They found that reducing RAC1 gene expression led to protection from developing the disease.

Ulcerative colitis is a chronic disease characterized by inflammation in the colon. It affects more than 250,000 Canadians. People living with ulcerative colitis experience a variety of symptoms including bloody stool, sudden urgency, stomach pain, cramps and nausea. It can also affect a child’s growth. Ulcerative colitis is managed by medications, surgery, as well as diet and lifestyle changes, but without treatment it can be debilitating and life-threatening.

“This discovery is particularly exciting because we didn’t just find a gene; we discovered its role in causing ulcerative colitis,” says Dr. Aleixo Muise, lead author of the study, Scientist and Staff Gastroenterologist at SickKids.

Patients with IBD who had increased expression of the RAC1 gene experienced increased inflammation in the colon. Research on animal models showed that when the gene was blocked or reduced, the experimental colitis was much less severe. The scientists found that blocking RAC1 expression led to reduced inflammation and protection from developing the disease.

“Understanding the genetics of IBD will help lead to novel diagnostic tools and treatments,” explains Muise, who is also Assistant Professor in the Department of Paediatrics at the University of Toronto. “The next step is to further comprehend the role of this gene and develop treatments that reduce the amount of RAC1 expression, or block it altogether.”

Muise adds that because RAC1 is expressed in most cell types and cell processes, it likely plays a role in other autoimmune diseases, like rheumatoid arthritis, psoriasis and diabetes.

"It is remarkable that RAC1 plays a conserved role in regulating immune responses from plants to man. This paper suggests that the immune pathways regulated by RAC1 are important for development of a human disease," explains Dr. John Brumell, Principal Investigator of the study and Senior Scientist in Cell Biology at SickKids.  

“As far as we know Jonathan will be taking medications for ulcerative colitis for the rest of his life,” says Bernie Wexler, Jonathan’s father. “My hope is that ongoing research will lead to improved treatments and ultimately improved quality of life for Jonathan and others who are living with ulcerative colitis.”

The study was funded by the Crohn’s and Colitis Foundation of Canada, Canadian Association of Gastroenterology, Canadian Institutes of Health Research, a Canadian Child Health Clinician Scientist Program award, an Early Researcher Award from the Ontario Ministry of Research and Innovation and SickKids 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 of Healthier Children. A Better World.™ For more information, please visit www.sickkids.ca

About Peter Gilgan Centre for Research and Learning 
The Peter Gilgan Centre for Research and Learning 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. The facility will physically connect SickKids science, discovery and learning activities to its clinical operations. Designed by award-winning architects Diamond Schmitt Architects Inc. and HDR Inc. with a goal to achieve LEED® Gold Certification for sustainable design, the Gilgan Centre will create an architectural landmark as the eastern gateway to Toronto’s Discovery District. The Peter Gilgan Centre for Research and Learning is funded by a grant from the Canada Foundation for Innovation, the Government of Ontario, philanthropist Peter Gilgan and community support for the ongoing fundraising campaign. For more information, please visit www.sickkidsfoundation.com/bepartofit.

For more information, please contact: 

Suzanne Gold 
The Hospital for Sick Children 
416-813-7654, ext. 2059 
suzanne.gold@sickkids.ca