School-led consortium identifies genomic regions that could influence severity of cystic fibrosis
| May 25, 2011 | |
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Biostatistics researchers from the University of North Carolina Gillings School of Global Public Health are among a team of researchers who have pinpointed regions of the human genetic makeup that contribute to the debilitating symptoms of cystic fibrosis (CF).
Their findings provide insight into the causes of the wide variation in lung disease severity experienced by CF patients. The work also may lead to new ways to diagnose and treat CF and more common lung diseases such as COPD (chronic obstructive pulmonary disease).
Dr. Fred Wright
Fred Wright, PhD, biostatistics professor at UNC’s Gillings School of Global Public Health, was lead author of the study, which appears in the journal Nature Genetics. The study was the work of the North America CF Gene Modifier Consortium, which brought together dozens of investigators from the United States and Canada to identify which regions of the genome are associated with lung disease severity in almost 3,500 CF patients. “This cystic fibrosis discovery showcases the valuable information that can be obtained when scientists work together on these genome wide association studies,” said Susan B. Shurin, MD, acting director of the National Heart, Lung and Blood Institute (NHLBI), which funded the study along with the Cystic Fibrosis Foundaton. “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 we are closer to finding new therapies.”
CF is a genetic disease that causes the lungs to clog up with thick, sticky mucus that is prone to infection. Although every CF patient carries mutations in both copies of the same gene, symptoms can vary widely from patient to patient. For example, some patients can have such severe lung disease that they are near death at age 10, whereas others can have nearly normal lung function at age 35.
“There is very good reason to believe that what we have discovered in CF lung disease could apply to other diseases as well,” said one of the senior study authors, Michael Knowles, MD, professor of pulmonary and critical care medicine at UNC School of Medicine.
For the last decade, Knowles and his colleagues have been searching for other genetic factors that modify the effects of the disease-causing mutations in the gene associated with CF, improving or exacerbating the disease as it unfolds. One way they have looked for these potential “genetic modifiers” has been through a candidate gene approach, methodically hand-picking their most likely candidates from the 20,000 or so genes in the human genome.
But that approach could be missing some key players. “Going after those candidate genes means relying on past basic and clinical data, and in some cases chasing ghosts and half-truths,” said lead study author Wright. “But when you step back and scan the entire genome, it is an unbiased look at what is there. In fact, both of the most significant genome-wide regions that we uncovered in this study are not ones that we would have necessarily predicted.”
The Consortium tested DNA from 2,464 CF patients and then replicated their findings in another 973 patients. They also performed a separate genome-wide linkage scan, which looks at how gene variants are inherited through multiple affected families. All of their results pointed to the same two regions of the genome.
Co-author Fei Zou, PhD, associate professor of biostatistics, added, “Biostatistics is quickly becoming key in genomics, and we could not have made sense of these data without rigorous analytic approaches.” Wright and Zou both emphasized the efforts of other biostatistics personnel, including assistant professor Wei Sun, PhD, who developed specialized software used by the group in its analyses.
Additional co-authors from the UNC biostatistics department include Ethan M. Lange, PhD, assistant professor; Gregory M. Mayhew, MS, biostatistics doctoral student; and Seunggeun Lee, PhD, recent graduate of the department.
Other UNC authors include Clayton W. Commander, PhD; Jingchun Luo, MD, MS; Wanda K. O’Neal, PhD; Rhonda G. Pace; and Jaclyn R. Stonebraker, PhD. Other key authors are Garry Cutting, MD, from Johns Hopkins University; Mitchell Drumm, PhD, from Case Western Reserve University; and Peter Durie, MD, from the University of Toronto.
More information is available on the Nature Genetics website.
UNC Gillings School of Global Public Health contact: Ramona DuBose, director of communications, (919) 966-7467 or ramona_dubose@unc.edu.
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