ARRA IMPACT REPORT:
Functional Genomics of Lung Diseases
Public Health Burden
Lung diseases cause more than 400,000 deaths annually in the United States and, in 2010, were responsible for approximately $186 billion in healthcare costs. Improved understanding of genetic and environmental factors involved in the development of lung diseases is urgently needed. This report focuses on idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and asthma.
Idiopathic Pulmonary Fibrosis (IPF)
IPF is an untreatable fibrotic lung disease of unknown etiology. Most patients survive only 2–5 years after diagnosis because their lungs become scarred and unable to transfer enough oxygen to the bloodstream. The disease affects approximately 200,000 Americans and accounts for 40,000 deaths annually. ARRA funds were used to identify a genetic factor that contributes to the development of IPF.
A large group of investigators led by a team at the University of Colorado compared genome sequences of 575 IPF patents with those of 322 healthy individuals. They found a mutation near a gene (MUC5B) that encodes for a major protein component of mucus secretions. Individuals carrying one copy of the mutation appear to have 9-fold increased risk of developing fibrosis in their lungs, and those with two copies have a 21-fold increased risk. Although the mutation alone does not always cause IPF (many genetic and environmental risk factors are probably involved), it is the strongest genetic risk factor for IPF discovered to date. The mutation was also shown to increase the odds of developing a hereditary form of IPF called familial pulmonary fibrosis (FPF) by 6- to 20-fold.1
To investigate how the mutation works in IPF patients, the scientists used additional information from an ARRA-funded project—the Lung Genome Research Consortium—in which a large volume of functional genomics data was generated, including comprehensive molecular measurements of lung tissues from 400 patients with IPF or chronic obstructive pulmonary disease. They found that the specific mutation responsible for IPF is in the promoter region of the MUC5B gene and that its presence increased the expression of the MUC5B gene 37-fold. Further research will be needed to identify other genetic factors associated with IPF and discover how they contribute to its development.
Cystic Fibrosis (CF)
CF is an inherited disease caused by mutations in the gene for a protein called cystic fibrosis transmembrane conductance regulator (CFTR). Chronic respiratory infections caused by the bacterium Pseudomonas aeruginosa have been linked to poorer lung function and shorter lifespan among CF patients. ARRA funds were used to identify genetic factors that may confer resistance or susceptibility to infection.
A project led by a team at the University of Washington sequenced all protein-coding portions of the genomes of two groups of people representing extremes of susceptibility to infection. The investigators discovered rare variations in the gene DCTN4 among CF patients most prone to early, chronic airway infections with Pseudomonas aeruginosa. The DCTN4 gene codes for dynactin 4, a protein that plays a role in bacterial clearance in cells. The discovery may suggest new targets for therapeutic intervention and enable development of more personalized treatment strategies.2
Asthma is a significant public health burden that afflicts 22 million Americans, including nearly 7 million children under six years of age. Direct and indirect costs associated with asthma exceed $13 billion per year. Ethnic and racial minority populations have an especially high prevalence of asthma and more severe disease. No approaches to prevent or cure asthma have been identified; existing treatments focus on controlling symptoms and preventing potentially life-threatening exacerbations. ARRA funding was used to address several critical issues in asthma.
NHLBI established a coordinated genetics/genomics program to delineate the genes and mutations involved in the development of asthma-related phenotypes and to explore specific gene-gene and gene-environment interactions that lead to different clinical manifestations and different individual responses to pharmacologic therapy. The vast amount of data collected through this project is being made widely available to other asthma researchers through a centralized repository, creating one of the world’s largest collections of asthma-related biological materials and genomic data for integrative genomics research. Future analyses may allow re-classification of asthma into more homogeneous subtypes of disease based on molecular signatures, deeper insights into disease pathogenesis, earlier diagnosis, improved prognosis, and personalized treatments.
ARRA funding also supported establishment of the EVE consortium, a national coalition of asthma genetics researchers in the U.S.to identify asthma-susceptibility genes in ethnically diverse populations. Genome-wide association data from nine institutions were pooled to create a large, shared dataset representing 5,416 individuals with asthma, with replication in an additional 12,649 individuals from the same ethnic groups. The researchers discovered a new genetic association with asthma that appeared in African Americans and African Caribbeans, but not in European Americans. The polymorphism, located in a gene called PYHIN1, may be the first identified asthma susceptibility gene variant that is specific to populations of African descent. The EVE consortium was also able to provide strong confirmation of four other gene variants suggested by a previous study (the 17q21 locus, and IL1RL1, TSLP, and IL33 genes). Confirmation of these associations in the highly diverse EVE population indicates that the gene variants are likely important in all racial/ethnic groups. Analyses by the EVE consortium are continuing and are expected to yield a more complete picture of the genetics of asthma in diverse populations and in specific groups.3
Contributing NIH Institutes & Centers
- National Heart, Lung, and Blood Institute (NHLBI)