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Researchers Identify Genes Linked to Worsening of Cystic Fibrosis

FIRST SINGLE GENE DISORDER STUDY SPANS 10 YEARS OF INTERNATIONAL COLLABORATION

May 23, 2011

CLEVELAND - A team of international researchers, including Case Western Reserve University School of Medicine, have discovered regions of the genome that affect the severity of the genetic disease cystic fibrosis (CF), the most common lethal genetic disease affecting children in North America. The findings provide insight into the causes of the wide variation in lung disease severity experienced by CF patients. It also points the way to new diagnostic markers and therapeutic approaches for this and more common lung diseases, such as asthma and COPD. “For the past four decades, the lives of CF patients have been extended tremendously, however they are still cut too short. This discovery of new gene variants provides new avenues to explore to extend their lives,” says Mitchell Drumm, PhD, professor of pediatrics and genetics and interim vice chair for research in the Department of Pediatrics at Case Western Reserve University School of Medicine and University Hospitals Rainbow Babies & Children’s Hospital.” This study, which appears online this week, in the journal Nature Genetics, is among the first reported genome-wide scans of a single gene disorder. It 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. CF is a genetic disease affecting every organ system, causes the lungs to clog up with infection-prone, thick, sticky mucus. Though every CF patient carries the CF gene, known as the cystic fibrosis transmembrane conductance regulator or CFTR, symptoms can vary widely from patient to patient. For instance, some patients can have such severe lung disease that they are near death at the age of 10, whereas others can have nearly normal lung function at the age of 35. For the last decade, Dr. Drumm and his colleagues have been searching for other genetic factors that modify the effects of the disease-causing mutations in the CFTR gene, either improving or exacerbating the disease as it unfolds. Genome-wide association studies, or "GWAS", as they are called, allow simultaneous examination of hundreds of thousands of genetic variants. The Consortium analyzed 570,725 variants across the chromosomes of 3,467 CF patients and found that variants in a small region of chromosome 11 and another small region on chromosome 20 consistently associated with the severity of a patient's lung disease. Members of the Consortium are now trying to understand how the variants in these regions affect the disease’s progression. “We have whittled down our scope from 30,000 genes down to four. For one of the genes we’ve identified, there are already medications on the market regulating it but for other conditions. We now have the opportunity to test existing drugs, ones that we never would have thought of but may in fact turn out to help 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, M.D., acting director of the NHLBI. “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, U.S. Cystic Fibrosis Foundation, Flight Attendant Medical Research Institute, Lawson Wilkins Pediatric Endocrine Society, Canadian Cystic Fibrosis Foundation, 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. Study co-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, Gregory Mayhew, Rhonda Pace, Jaclyn Stonebraker, Wei Sun, Fei Zou, Wanda O’Neal, and Michael 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; Katrina Goddard of Oregon Clinical Translational Research Institute; Jack Kent, Jr. and John Blangero of Southwest Foundation for Biomedical Research; Peter Pare and Andrew Sandford of the University of British Columbia, Vancouver, Canada; Lori Vanscoy of Naval Medical Center.

Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.

Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."

The School of Medicine is affiliated with University Hospitals Cleveland Medical Center, MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. case.edu/medicine.