A common polymorphism in the promoter of a mucin gene, MUC5B rs35705950, is significantly associated with improved survival in patients who have idiopathic pulmonary fibrosis, according to a report published online May 21 in JAMA.
The 2-year cumulative rate of death was lower among IPF patients who carried one or more copies of this variant than in those who did not in a cohort of 438 patients, and this finding was replicated in a validation cohort of another 148 patients, said Anna L. Peljto, Dr.P.H., of the department of epidemiology, University of Colorado School of Public Health, Denver, and her associates.
Dr. Anna Peltjo
Their report was published simultaneously with its presentation at the annual meeting of the American Thoracic Society.
Paradoxically, this same polymorphism was previously reported to be strongly associated with the development of both sporadic IPF and familial interstitial pneumonia, and is considered a risk allele for these disorders.
It is not yet known how the MUC5B rs35705950 polymorphism confers a survival advantage in IPF, but "enhanced mucosal host defense, reduction in infectious complications, a beneficial drug response, and a potential dual role in wound repair should all be considered," the investigators said.
"Regardless of the mechanism, the results suggest that patients with IPF with the MUC5B promoter polymorphism may represent a pathogenically distinct disease entity that incorporates both a significantly higher predisposition to disease and a significantly longer survival," they noted.
Dr. Peljto and her colleagues examined whether carrying this variant affected survival by analyzing data on 438 patients who participated in a 3-year study of interferon treatment for IPF. A total of 37% of study participants were found to carry the MUC5B polymorphism.
The unadjusted 2-year cumulative incidence of death was lower in patients who carried one or more copies of the variant than in those who did not.
The researchers then assessed the polymorphism in a second population: 148 patients treated at the interstitial lung disease clinic at the University of Chicago beginning in the late 2000s and followed for a median of 1.6 years. The frequency of the MUC5B polymorphism was 39%, similar to that in the first cohort.
The unadjusted cumulative incidence of death also was significantly lower in patients who carried the genetic variant in this cohort.
The data from both groups were pooled and adjusted for patient age, sex, smoking history, forced vital capacity at baseline, and diffusing capacity of carbon monoxide at baseline.
"The MUC5B genotype remained a statistically significant predictor of survival," Dr. Peljto and her associates said.
The data were adjusted further to account for study subjects’ plasma concentrations of matrix metalloproteinase-7 (MMP-7); high levels of this substance are associated with poor outcomes in IPF. The association between the MUC5B polymorphism and improved survival remained constant in this analysis.
"This study is, to our knowledge, the first to demonstrate that a genetic variant is associated with survival in IPF," the researchers said (JAMA 2013 May 21 [doi:10.1001/jama.2013.5827]).
However, it would be premature to consider routine clinical genotyping of IPF patients at this time, "given that the addition of MUC5B resulted in relatively small gains in predictive accuracy in patients with established disease."
It may be helpful to combine the predictive value of MUC5B with other genetic and molecular factors to obtain a prognosis in patients who have subclinical or early-stage disease, before lung function has declined notably. "This is especially important because there are currently no IPF pharmalogical therapies approved for use in the United States, and opportunities for early genetic counseling or lung transplantation may be a patient’s only recourse," the investigators said.
This study was supported by the National Heart, Lung, and Blood Institute and the Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research at the University of Pittsburgh. Dr. Peljto reported no relevant financial conflicts; her associates reported numerous ties to industry sources.