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Study Proves Genetic Variations Influence Cystic Fibrosis' Severity

Date:
October 6, 2005
Source:
University of North Carolina at Chapel Hill
Summary:
Subtle differences in other genes -- besides the defective gene known to cause the illness cystic fibrosis -- can significantly modify the inherited disease's severity, a large new multi-center national study has concluded.
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CHAPEL HILL -- Subtle differences in other genes -- besides thedefective gene known to cause the illness cystic fibrosis -- cansignificantly modify the inherited disease's severity, a large newmulti-center national study has concluded.

The study, led by University of North Carolina at Chapel Hill andCase Western Reserve University researchers, for the first time showsthat particular versions of the transforming growth factor beta 1(TGFb1) gene are largely responsible for how badly the illness affectspatients' lungs.

A report on the findings appears in the Oct. 6 issue of the New England Journal of Medicine.

"As this gene is one of about 30,000 genes in our bodies, itsidentification as a modifier of the CF lung disease allows us aspecific target to focus on for improving CF therapy," said Dr.Mitchell L. Drumm, associate professor of pediatrics and genetics atCase. "As we better understand its function in lung disease, we hope itwill allow us to design better and more specific therapies. Becauseother researchers have found a similar effect of this gene in asthma,the implications likely extend to other disorders affecting the lungsas well."

More than 50 hospitals and medical centers and scores ofphysicians across the United States and Canada participated in theinvestigation, which was actually two closely related studies withseparate groups of patients. Findings were essentially the same forboth, according to principal investigator Dr. Michael R. Knowles,professor of medicine at the UNC School of Medicine.

"This study is especially important in the field of geneticmodifiers, because we had enough patients -- over 1,300 -- and a robuststudy design to assure that our observation is likely correct," Knowlessaid. "That is in contrast to much of the previous work in this areawhere the number of subjects was usually too small to be conclusive.

"The observation has tremendous implications about the futurefor prognosis and potential new therapies in CF," he said. "We are onthe verge in the next two or three years of being able to test forother such genetic variants across the entire human genome. Our hope isto be able to identify most of the important gene modifiers in CF sothat they can be used for prognosis, the identification of noveltherapeutic targets and perhaps even directing therapy in an individualpatients toward different types of adverse gene modifiers."

Initially, the study involved 808 cystic fibrosis patients whohad inherited an altered form of a gene known as delta F508 from bothparents. The second study involved 498 people with the condition. Bymeasuring the volume of air when patients' exhaled strongly into amachine, researchers determined how severe each subject's lung diseasewas.

Scientists then correlated patients' level of illness againstvarious genetic mutations and found that variants of a gene known asTGFb1 were associated with worse disease. The findings appear toexonerate certain other previously suspected mutations.

Besides Drumm and Knowles, authors of the report include Drs.Fred A. Wright and Fei Zou, associate professor and assistant professorof biostatistics, respectively, at the UNC School of Public Health,and, at Case, Drs. Mark D. Schluchter and Michael Konstan, professorsof pediatrics; and Dr. Katrina Goddard, associate professor ofepidemiology and biostatistics. Thirteen other scientists andclinicians also contributed to the work and were listed as co-authors.

In an accompanying editorial, Drs. Christina K. Haston andThomas J. Hudson of McGill University in Montreal praised the newstudy.

"There are many lessons about modifier genes to be extrapolatedfrom this study, starting with recognition of the tremendous importanceof the study design," Haston and Hudson wrote.

Among its strengths, they said, were its large size -- which isessential for such studies if they are to be useful -- that it focusedon a single class of gene variation and that it took into accountnumerous possible confounders such as sex, other illnesses likeasthmas, enrollment sites, associated diseases and infections.

"There are likely a number of gene modifiers in CF and otherdiseases, and this current paper describes one of the first robustexamples," Knowles said. "Some CF patients may do worse because of'severe inflammation' genes, whereas others may do worse because ofdifferences in mucus genes. Still others might because of their growthand metabolism genes, etc... Thus, therapy might need to be targeted toa particular area or areas in individual patients. This is importantnot only for CF, but for other lung diseases as well because genemodifiers we discover in CF will be seen in other diseases, and thereare already examples of that."

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Support for the investigations came from the Cystic FibrosisFoundation, the National Institutes of Health, Genome Canada and theCanadian Cystic Fibrosis Foundation.

Additional support came from the UNC School of Medicine'sgenetics department and Dr. William F. Marzluff, executive associatedean for research at the medical school and professor of biochemistryand biophysics.



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Materials provided by University of North Carolina at Chapel Hill. Note: Content may be edited for style and length.


Cite This Page:

University of North Carolina at Chapel Hill. "Study Proves Genetic Variations Influence Cystic Fibrosis' Severity." ScienceDaily. ScienceDaily, 6 October 2005. <www.sciencedaily.com/releases/2005/10/051006084732.htm>.
University of North Carolina at Chapel Hill. (2005, October 6). Study Proves Genetic Variations Influence Cystic Fibrosis' Severity. ScienceDaily. Retrieved October 14, 2024 from www.sciencedaily.com/releases/2005/10/051006084732.htm
University of North Carolina at Chapel Hill. "Study Proves Genetic Variations Influence Cystic Fibrosis' Severity." ScienceDaily. www.sciencedaily.com/releases/2005/10/051006084732.htm (accessed October 14, 2024).

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