Common Genetic Variant Linked to Pulmonary Fibrosis Risk
Posted Apr 21 2011 8:27pm
Scientists funded by the National Institutes of Health have identified
a common genetic variant associated with substantially increased risk
of developing pulmonary fibrosis, a debilitating and life-threatening
lung condition. The genetic variant is found in a region of DNA thought
to regulate the production of an important mucus-forming protein.
However, knowing the gene variant is not, by itself, enough for a test
to determine who would be at risk of the disease, experts say.
This genetic variant near the mucin 5B gene, termed rs35705950, is both
fairly common and a risk factor for idiopathic pulmonary fibrosis (IPF)
and familial interstitial pneumonia (FIP). IPF and FIP are two related
lung diseases that produce progressive, irreversible, and currently incurable
scarring of the lungs, which is called fibrosis.
The study, published April 21 in the New England Journal of Medicine,
compared the gene sequences of 575 individuals affected by IPF (492)
or FIP (83) as well as 322 healthy people.
The researchers found that more than half of the IPF/FIP study participants
have at least one copy of the variant, compared to one in six healthy
controls who have the variant. Those with one copy have approximately
five- to eightfold increased odds of developing fibrosis in their lungs,
compared to those without the genetic variant. Individuals who have two
copies of the variant have approximately twentyfold greater odds of developing
fibrosis in their lungs.
This study highlights how an investment in genomics can really pay
off, said Susan Shurin, M.D., acting director of NIHs National Heart,
Lung, and Blood Institute (NHLBI), one of the major funders of this research. With
this discovery we are one step closer to understanding these serious
and mysterious diseases that affect over 100,000 Americans.
However, she cautioned that this variant alone cannot predict disease
risk for an individual. Many people who have the variant still have healthy
lungs, so genetic testing for rs35705950 alone is unlikely to help doctors
to diagnose their patients. As yet unknown modifying genetic and/or environmental
factors are likely to affect development of disease in persons who possess
the genetic variant.
Since the risk of IPF or FIP in the general population is low, the absolute
risk — the likelihood that an individual will have the condition — is
still low, even for those with the variant.
Nevertheless, this discovery has immediate importance for scientists
who study pulmonary fibrosis, since it may point to the root causes of
IPF and FIP and to new ways to prevent and manage these conditions. The
genetic alteration identified by the multi-institution research team,
led by researchers at National Jewish Health in Denver, occurs in a region
called the promoter, near the mucin 5B gene. The promoter region regulates
gene expression, and the identified variant ramps up the production of
mucin 5B protein, causing normal lungs to produce over 35 times as much
of this mucus-forming protein compared to controls.
This possible association between mucus production and fibrosis shows
how these new genomic technologies can open up new ways of thinking about
diseases, said James Kiley, Ph.D., director of NHLBIs Division of Lung
Diseases. Down the road, this discovery will help us uncover how pulmonary
fibrosis develops, and potentially lead to new treatments.
In addition to National Jewish Health, other research sites involved
in this study are the University of Colorado Denver School of Medicine;
University of Colorado Denver, School of Public Health; Duke University
Medical Center, Durham, N.C.; Vanderbilt University School of Medicine,
Nashville; Landspitali University Hospital, Reykjavik, Iceland; University
of Texas M. D. Anderson Cancer Center, Houston; National Institute of
Environmental Health Sciences (NIEHS), part of the NIH, Research Triangle
Park, N.C.; North Carolina State University, Raleigh; and University
In addition to NHLBI support, a large part of this study was conducted
at the NIEHS Intramural Research Program, and the research was also supported
by a grant from the National Cancer Institute, part of the NIH.
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