Modifier genes may identify severity of cystic fibrosis

In an age when 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 patients with cystic fibrosis (CF) that may be responsible for variation in disease severity. This is the first study to show evidence that modifier genes affect the severity of cystic fibrosis.

The scientists set out to find out why some patients have a good quality of life, while others who carry the same mutations in CF genes experience severe lung disease, need of lung transplants or die. Their discovery of modifier genes may eventually lead to treatment that are tailored to patients, according to their individual disease. The study is reported in the 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 with researchers and 37 CF clinics across Canada to obtain DNA and information about the lungs, intestine, liver and pancreas of 75% of the Canadian CF population. After discovering that their colleagues at 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 CF 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 CF gene, disease severity and lung function decline can differ substantially. We know that these patients all have CF, but the rate at which their lungs are deteriorating is variable.”

Back in 1989, SickKids scientists discovered the CF transmembrane conductance regulator (CFTR) – the gene that causes the disease.   In CF, 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 CF 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, CF 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 CF of each individual before they get symptoms and to base their treatment on knowledge of their genetic makeup, thus preventing disease progression.

“We know that CF 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.”

CF 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, and SickKids Foundation.