Home > Media & news > Gene Linked to Lung Fibrosis and Its Survival

Gene Linked to Lung Fibrosis and Its Survival

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: May 21, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

PHILADELPHIA — A common genetic variant increases the risk of pulmonary fibrosis but also predicts better survival in idiopathic cases, researchers found.

Each copy of the rs35705950 allele in a gene that encodes for gel-forming mucin (MUC5B) was independently associated with 6.8 times higher odds of definite CT evidence of pulmonary fibrosis (P<0.001), David A. Schwartz, MD, of the University of Colorado in Aurora, and colleagues reported online in the New England Journal of Medicine.

But carrying one copy of that polymorphism was also associated with 52% to 61% better odds of survival in idiopathic pulmonary fibrosis, they reported in a separate study online in the Journal of the American Medical Association. Two copies conferred 77% to 85% better odds of survival.

Both studies were presented here at the American Thoracic Society meeting.

These genetic findings move the search for a cause of the mysterious disease toward environmental factors, according to an editorial accompanying the NEJM paper.

“For the past 20 years, most research into idiopathic pulmonary fibrosis has been directed at the cellular and signaling events that drive fibrosis,” wrote William Cookson, MD, DPhil, and Miriam Moffatt, DPhil, both of the National Heart and Lung Institute at Imperial College London.

“The results reported in the Journal prompt a rethinking about the disorder, since they suggest the presence of a spectrum of fibrotic diseases in which secreted mucins play a major role.

“The known role of mucins in providing an effective mucosal barrier, the contribution of surfactant mutations to familial idiopathic pulmonary fibrosis, the effects of cigarette smoking, and the observation that idiopathic pulmonary fibrosis is confined to the lung all suggest an important environmental component to the disease.”

Chronic occult infection — bacterial, viral, or fungal — should be high on the list of suspects, Cookson and Moffatt suggested.

“The high penetrance of the MUC5B susceptibility allele suggests that any environmental factor is likely to be common,” they added.

Schwartz’s group found a minor risk allele in 11% of the general population studied in the Framingham Heart Study. Their analysis included 2,764 adults with CT chest scans as part of the longitudinal study’s third-generation and offspring cohorts.

In their analysis of two idiopathic pulmonary fibrosis cohorts, the prevalence was higher.

Among 438 cases in the INSPIRE trial of interferon-gamma 1b, 59% carried one copy of the risk allele and 7% carried two copies.

Among 148 cases from the Interstitial Lung Disease Clinic at the University of Chicago, the frequency was 66% and 6%, respectively.

Carriers in the Framingham study were more likely to be among the 7% with at least some evidence of interstitial lung abnormalities, with a 2.8-fold higher odds per copy number of the minor rs35705950 allele after adjustment for covariates (P<0.001).

“The common association between MUC5B genotype, idiopathic pulmonary fibrosis, and now a phenotype in the general population that includes abnormalities on imaging, physiological abnormalities, and gas-exchange abnormalities suggests that, in at least some cases, interstitial lung abnormalities may represent an early or subclinical stage of pulmonary fibrosis,” the group explained in the NEJM.

The link was greater after age 50, although a history of cigarette smoking didn’t reach statistical significance as a factor.

In those with idiopathic pulmonary fibrosis, the unadjusted incidence of mortality over 2 years of follow-up fell with the number of copies of that risk allele, though.

After adjustment for age, sex, smoking history, and baseline lung capacity and function, the odds of survival were:
  • In the INSPIRE cohort, 0.48 for one copy and 0.23 for two compared with no copies (P<0.001)
  • In the Chicago cohort, 0.39 with one copy and 0.15 with two compared with no copies (P<0.002)

The explanation may be that the idiopathic pulmonary fibrosis that arises from other non-MUC5B causes has a different mechanism and poorer prognosis, the researchers noted in the JAMA paper.

Lead time bias and survivor bias were unlikely based on patient characteristics, they pointed out.

The effect was also independent of plasma levels of matrix metalloproteinase 7 (MMP-7, which has been linked to survival) and treatment status with interferon in INSPIRE.

Adding MUC5B genotype to a predictive model of clinical and physiologic parameters significantly improved the accuracy of mortality prediction in both cohorts (P<0.001 in INSPIRE and P=0.01 in the Chicago cohort).

But the gains were relatively small, so routine clinical genotyping would be premature in established disease, Schwartz’s group cautioned. It might be worth looking at for subclinical and early stage disease, though, they suggested, “because there are currently no IPF pharmacological therapies approved for use in the United States, and opportunities for early genetic counseling or lung transplantation may be a patient’s only recourse.”

Limitations included assessment of all cause- rather than lung fibrosis-related mortality and lack of data on other genetic and serum markers in the idiopathic pulmonary fibrosis cohorts. In the Framingham general population cohort, limitations were sample size, possible misclassification of lung abnormalities, and the lack of racial and ethnic diversity.

SOURCE: http://www.medpagetoday.com/MeetingCoverage/ATS/39316

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