Some Idiopathic Pulmonary Fibrosis May Have Genetic Cause

March 29, 2007

BALTIMORE -- Some cases of idiopathic pulmonary fibrosis may be the result of genetic flaws rather than autoimmune disease, according to researchers here.

BALTIMORE, March 29 -- Some cases of idiopathic pulmonary fibrosis may be the result of genetic flaws rather than autoimmune disease, according to researchers here.

About 8% of a group of patients with an inherited form of the disease have genetic mutations that result in shortened telomeres, the ends of chromosomes, reported Mary Armanios, M.D., of Johns Hopkins, and colleagues, in the March 29 issue of the New England Journal of Medicine. Those shortened telomeres lead to the loss of alveolar cells and the onset of fibrosis.

The finding may have clinical implications, either for more tailored treatments or for earlier diagnosis in some cases, Dr. Armanios and colleagues wrote.

"For many years, we've thought that (idiopathic pulmonary fibrosis) is caused by an immune attack against the lungs, even though current therapies aimed at dampening the immune system don't work," Dr. Armanios said in a statement.

"If we're not so tied to immune suppression therapies, we could eventually tailor drugs to a different target," she said.

The finding arose from the observation that some people with the rare hereditary condition dyskeratosis congenita develop fatal pulmonary fibrosis, the researchers said.

That condition is known to be caused by dominant mutations in two genes -- hTERT and hTR, which encode telomerase reverse transcriptase and telomerase RNA, respectively.

"Since familial idiopathic pulmonary fibrosis is also dominantly inherited, we hypothesized that telomere shortening causes this disease and that mutations in telomerase may contribute to it," the researchers said.

Dr. Armanios and colleagues screened 73 members of the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in the two genes. They found:

  • Six (8%) had mutations in one or the other of the two genes.
  • In the six families, mutations were present in affected members, but generally absent in asymptomatic members in the same generation.
  • The mutation was present in apparently unaffected family members, but they tended to be on average 11 years younger than the affected members had been at the time of diagnosis.

The average telomere length in lymphocytes was significantly shorter in affected member (P=0.006) than in relatives who did not carry the mutation. The average length for non-carriers was six kilobases, compared with four kilobases for carriers of the mutations.

When compared with 400 healthy controls, the average telomere length in participants with the disease was below the 10th percentile, a difference that was significant at P=0.0018.

None of the participants with the disease showed symptoms of dyskeratosis congenita, Dr. Armanios and colleagues said, and their clinical presentation was indistinguishable from others with idiopathic pulmonary fibrosis.

Dr. Armanios said there may also be a link between short telomeres and patients with a non-familial form of the disease, although teasing that out will require larger studies.

"There may be other causes for short telomeres, such as older age and smoking, which also happen to be the main risk factors for (idiopathic pulmonary fibrosis)," she said.