A genetic variant in the MUC5B gene appears to be associated with both idiopathic pulmonary fibrosis and familial interstitial pneumonia, according to a report in the April 21 issue of the New England Journal of Medicine.
The MUC5B gene encodes mucin 5B, a gel-forming protein that is usually found in the lungs and is overexpressed in pulmonary diseases such as asthma, bronchitis, chronic obstructive pulmonary disorder, and cystic fibrosis. "In the aggregate, our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis," said Max A. Seibold, Ph.D., of National Jewish Health, Denver, and his associates.
In addition, the link with familial interstitial pneumonia "could provide insight into the particular clinical manifestations of this complex disease process and consequently lead to earlier detection, more predictable prognosis, and personalized therapeutic strategies," they said.
Until now, the genetic mutations that have been implicated in both idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) have accounted for only a small proportion of the population risk for the disorders. The investigators searched further for other related mutations, beginning with a genomewide linkage scan in 82 families with FIP.
The results led the researchers to assess genetic variation in particular regions of three gel-forming mucin genes, using blood samples from a separate cohort of 83 subjects who had FIP, 492 subjects who had IPF, and 322 controls. One single-nucleotide polymorphism (SNP) in the putative promoter of the MUC5B gene was particularly strongly associated with both disorders. The minor allele of this SNP (rs35705950) was found at a frequency of 34% among subjects with FIP and 38% among those with IPF, compared with only 9% among controls.
A subsequent analysis demonstrated that rs35705950 exerted an effect in both disorders that was strongly independent of that of other, known mucin variants.
Next, the investigators evaluated the effect of rs35705950 on MUC5B expression in lung tissue from 33 subjects with IPF and 47 control subjects. They found that MUC5B expression was 14 times higher in samples from affected patients than in those from control subjects.
Finally, immunohistochemical staining of the lung tissue from IPF patients showed regions of dense accumulation of MUC5B in areas of microscopic honeycombing that are characteristic of IPF lesions. There was patchy staining of the metaplastic epithelia lining the honeycomb cysts, and of the mucous plugs within the cysts, the investigators said (N. Engl. J. Med. 2011;364:1503-12).
"The prevailing opinion is that IPF develops as a result of excessive, sequential lung injury or aberrant wound healing." The mechanisms by which this genetic variant interacts with excessive lung injury or aberrant repair is not yet known, they added.
"Our results could potentially alter the clinical approach to interstitial pneumonia," Dr. Seibold and his colleagues said.
"The implication of secreted airway mucins in the pathogenesis of [pulmonary fibrosis] suggests that the air space plays a role in the development of idiopathic [interstitial pneumonia]. Although identification of rs35705950 ... can be used to target persons at risk for the development of idiopathic [interstitial pneumonia] (especially those who are members of families subject to idiopathic [interstitial pneumonia]), our observations that the biologic features of mucins may be important etiologic factors in this disease could reorient the focus of pathogenic and therapeutic studies in interstitial lung disease to lung mucins, the air space, and the bronchoalveolar unit," they noted.
This study was supported by the National Institute of Environmental Health Sciences, the National Cancer Institute, the American Lung Association, the Cystic Fibrosis Foundation, the Chapman Foundation, InterMune, and the National Heart, Lung, and Blood Institute. Dr. Seibold’s associates reported ties to numerous academic, government, and industry sources. Dr. Boucher reported ties to Parion Sciences, Inspire Pharmaceuticals, and Pulmatrix.