Researchers discover new genes that influence severity of cystic fibrosis

May 23 2011

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, the 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 as 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 team is eager to study further these candidate genes to pin down exactly how they alter the severity of CF. "Of course we want to continue to push the median life expectancy up so that hopefully patients with more severe cases of CF will, with multimodal therapy, survive longer," says Cutting. "And this is the first step toward developing such therapies for these patients.