Gene Variant Heightens Risk of Severe Liver Disease in Cystic Fibrosis

Toronto, Ontario (September 9, 2009) – Researchers funded by the Canadian Cystic Fibrosis Foundation and Genome Canada at The Hospital for Sick Children (SickKids), the University of Toronto and the University of North Carolina at Chapel Hill have discovered a genetic risk factor for severe liver disease in children and adults with cystic fibrosis.

Those who carry a particular variant of the SERPINA1 gene (also known as alpha-1-antitrypsin or alpha-1-antiprotease) are five times more likely to develop cirrhosis and other liver complications than patients who carry the normal version of the gene.

The study, which appears in the Sept. 9 issue of the Journal of the American Medical Association (JAMA), could lead to earlier detection and diagnosis of liver disease in people with cystic fibrosis, and better treatment options for the patients affected by the disease. In addition, it could pave the way for similar studies in more common forms of liver disease.

“This is a landmark study in that it raises the possibility of being able to identify patients with cystic fibrosis who are destined to develop liver disease,” says Dr. Peter Durie, co-principal investigator of the study, Gastroenterologist and Senior Scientist at SickKids, and Professor of Paediatrics at the University of Toronto. “Further research in this area will hopefully lead to earlier and better treatment options for these patients.”

Cystic fibrosis is the most common fatal genetic illness among young Canadians. In this disease, defects in the CFTR gene cause the lungs, intestines and pancreas to become clogged with mucus, resulting in breathing problems and other difficulties. Though every person with cystic fibrosis carries mutations in both copies of their CFTR gene (one inherited from the mother and one from the father), symptoms can vary widely from patient to patient. For instance, about five per cent of individuals with cystic fibrosis develop liver disease so severe it requires a liver transplant.

For the last decade, researchers have investigated what other genetic factors might modify the effects of the disease-causing mutations in the CFTR gene, further altering the biological conditions under which the disease unfolds to either make it milder or more severe. Several genes have emerged as potential “genetic modifiers,” and studies to replicate some of those findings have recently been conducted.

In this new study, an international team of scientists compiled the largest-ever number of samples from cystic fibrosis patients with severe liver disease. The study was initially conducted in 124 cystic fibrosis patients with severe liver disease and 843 cystic fibrosis patients without liver disease. The team evaluated nine sequence variants in five genes that previous studies had suggested might be associated with liver disease.

The researchers found that more cystic fibrosis patients with liver disease had a particular version of the SERPINA1 gene -- called the Z allele – than patients without liver disease, indicating that the gene variant plays a role in the development of this ailment. The researchers confirmed their results in a separate set of cystic fibrosis patients, 136 with liver disease and 1088 without.

Aided by their international collaborators, the researchers are now searching for genetic modifiers associated with other complications of cystic fibrosis, including lung disease, intestinal obstruction and diabetes.

This discovery comes 20 years after another important breakthrough in CF research: in 1989, a SickKids-led team of researchers, funded by the CCFF, made medical history when they identified the gene responsible for cystic fibrosis.

“This new finding exemplifies the power of genomics, and the resulting and relatively recent shift from investigating disease by examining single genes in a few patients to using large-scale approaches to simultaneously analyze the contributions to disease development of multiple genes and their products across a broad population of patients,” added Christian Burks, PhD, President & CEO of the Ontario Genomics Institute, which helped fund the study. “The discovery and characterization of this gene variant by Dr. Durie and his team is an exciting harbinger for a new era in predictive molecular diagnostics and personalized medicine.”

The study was funded in part by the Canadian Cystic Fibrosis Foundation and Genome Canada through the Ontario Genomics Institute. CCFF-funded researchers involved in the study include Dr. Peter Durie, Mary Corey, PhD, and Julian Zielenski, PhD. Additional SickKids participants include Dr. Simon Ling, Dr. M. James Phillips and Ruslan Dorfman PhD.

About the Canadian Cystic Fibrosis Foundation
The Canadian Cystic Fibrosis Foundation is a Canada-wide health charity, with 50 volunteer chapters, that funds CF research and care. In 2009, the Foundation is supporting more than 50 research projects which are exploring all aspects of the CF puzzle; from investigating new methods of fighting infection and inflammation in the lungs to finding new therapies that target the basic defect at the cellular level.

About The Hospital for Sick Children
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 www.sickkids.ca. SickKids is committed to healthier children for a better world.

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For more information, please contact:

Sagal Ali
Media Relations Officer
Canadian Cystic Fibrosis Foundation
1-800-378-2233 ext. 290
sali@cysticfibrosis.ca
www.cysticfibrosis.ca

Suzanne Gold
Communications Specialist – Media Relations
The Hospital for Sick Children
416-813-7654 ext. 2059
suzanne.gold@sickkids.ca
www.sickkids.ca

Reviewed/updated: 2009-09-14