Johns Hopkins Institute for Genetic Medicine researchers working as part of the North American Cystic Fibrosis Consortium have discovered two regions of the genome that affect the severity of cystic fibrosis, a genetic condition that causes scarring throughout the body, affecting most notably the pancreas and lungs. Reporting online this week in Nature Genetics, the team describes the first-ever study to identify genetic variations that are associated with more severe cases of CF.
“We already know which gene causes CF, but to a large extent that gene does not by itself explain how severe the condition will be,” says Garry Cutting, M.D., a professor of pediatrics and member of the McKusick-Nathans Institute for Genetic Medicine at Johns Hopkins. “Now we’ve discovered new genes that influence the course of disease and may enable prediction of disease severity and, most importantly, customization of treatments for patients with unfavorable genetic modifiers — this is the realization of individualized medicine.”
This study used samples from 3,467 patients that included unrelated patients from the Genetic Modifier Study out of University of North Carolina at Chapel Hill, unrelated patients from the Canadian Consortium for Genetic Studies out of University of Toronto, and related patients and their parents from the CF Twin and Sibling Study at Johns Hopkins. “Most CF patients born today live to their mid-30s, but that’s an average. Some succumb to the disease before their tenth birthday while others live into their 50s and we wanted to know why,” says Cutting. “To achieve this goal, we had to work together one group.”
To do this, the three research groups had to first agree on how they were comparing disease severity, for which they used a measure of how much air a patient could breathe out forcefully in one second, then developed a standard by which they could compare patients of different ages. They then agreed on using the same technology to genotype patient DNA and analyze 600,000 sites of variation within the genome. Using these data, the researchers looked for common variations that are associated more frequently with severe cases of CF, which led to a discovery of a region encompassed by two genes on chromosome 11. Analysis of the related patients revealed a second region on chromosome 20 that was linked to the disease. Further analysis of this region reveals five genes, all of which are turned on in cells of the respiratory system and some of which are known to play a role in inflammation.
The Hopkins team is eager to determine which of the genes on chromosome 20 alters the severity of CF. “Our long-term goal is to extend the median life expectancy so that hopefully patients with more severe cases of CF will survive as long as those with milder forms of the disease,” says Cutting. “And this is the first step toward developing such therapies for these severe patients.
“This cystic fibrosis discovery showcases the valuable information that can be obtained when scientists work together on these genome wide association studies,” says Susan B. Shurin, M.D., acting director of the National Heart, Lung and Blood Institute. “Now we are closer to understanding why patients with the exact same genetic mutation in the cystic fibrosis gene have such widely varying manifestations of lung disease, and closer to finding new therapies.”
This study was funded by the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases the U.S. 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, Lloyd Carr-Harris Foundation, and Joint Fellowship of Canadian Institutes of Health Research and Ontario Women’s Health Council.
Authors on the paper are Vishal Doshi, Scott Blackman, J. Michael Collaco, Deanna Green, Kathleen Naughton and Garry Cutting of Johns Hopkins; Fred Wright, Clayton Commander, Ethan Lange, Seunggeun Lee, Jingchun Luo, Gergory Mayhew, Rhonda Pace, Jaclyn Stonebraker, Wei Sun, Fei Zou, Wanda O’Neal, and Michale Knowles of University of North Carolina at Chapel Hill; Lisa Strug, Andreea Cojocaru, Mary Corey, Ruslan Dorfman, Weili Li, Johanna Rommens, Chelsea Taylor, Julian Zielenski, and Peter Durie of the Hospital for Sick Children, Toronto, Ontario, Canada; Lei Sun of the University of Toronto, Ontario, Canada; Yves Berthiaume of l’Universite de Montreal, Quebec, Canada; David Cutler of Emory University, Atlanta, Ga.; Katrina Goddard of Oregon Clinical Translational Research Institute, Portland, Or.; Jack Kent, Jr. and John Blangero of Southwest Foundation for Biomedical Research, San Antonio, Tx.; Peter Pare and Andrew Sandford of the University of British Columbia, Vancouver, Canada; Lori Vanscoy of Naval Medical Center, Portsmouth, Va.; Mitchell Drumm of Case Western Reserve University, Cleveland, Oh.