A variant of the MUC5B gene, known as the rs35705950 (T) allele, appears to lead to better survival in people with idiopathic pulmonary fibrosis (IPF) on anti-fibrotic treatment, a study reports.
These findings highlight the potential usefulness of MUC5B genetic data in treating and managing these patients.
Although the causes of IPF are unknown, between 30% and 40% of all patients have a specific variation in the MUC5B gene called rs35705950 (T) allele, where a nucleotide (the building blocks of DNA) guanine (G) is substituted by a thymine (T).
This mutation, the study noted, “represents the strongest genetic risk factor for sporadic and familial IPF described thus far.”
Several conflicting reports have emerged on the prognostic value of the rs35705950 variant in people with IPF. While some studies have shown that this mutation is linked to increased mortality, others showed the opposite. Of note, these studies were carried out before anti-fibrotics became widely prescribed.
A team of scientists at the University of Padova, in Italy, set out to determine how the presence of the MUC5B rs35705950 variant affects IPF progression in people on anti-fibrotic treatment.
“To the best of our knowledge, this has never been investigated before,” the researchers wrote.
A group of 88 of these IPF patients — being treated either with Genentech’s Esbriet (pirfenidone) or Boehringer Ingelheim’s Ofev (nintedanib) — were followed from April 2014 until lung transplant, death, or their study’s end in December 2019. Patients had a mean age at diagnosis of 70, most were men (81%, 71 people), and 59 (67%) were former smokers.
Reductions of 5% or more per year in forced vital capacity (FVC), a measure of the maximum volume of air a person can exhale after a full inhalation, was established as disease progression.
The mean FVC at baseline was 77%, suggesting a mild loss of lung function. During the first year of treatment with anti-fibrotics, 63 patients (72%) stayed functionally stable, and 25 (28%) showed disease progression.
Over the course of this study, 27 patients (31%) died, five (6%) underwent lung transplants, and five (6%) experienced an acute exacerbation, or sudden symptom worsening.
DNA was extracted from each patient to identify the type of MUC5B rs35705950 variation present. Patients were divided into two groups based on the absence or presence of the minor allele (T): 61 patients (69%) carried the mutant T allele (genotype TT or TG), while 27 others (31%) did not (genotype GG).
Patients with the GG type smoked for longer than those with TT/TG — 30 pack-years versus 10 pack-years. (A pack-year is defined as smoking 20 cigarettes, or one pack, each day for one year.) Although their FVC was lower at the start of treatment, FVC decline at a first year of treatment use was similar between the two groups.
Those in the TT/TG group experienced respiratory failure at rest later than those in the GG group, 31 vs. 24 months. Respiratory failure was defined as blood-oxygen levels lower than 60 mmHg.
Researchers found that respiratory failure at rest occurring early (before 26 months) was independently linked to disease progression and mortality.
The length of time patients lived with IPF until worsening (progression-free survival) was similar between the two groups — a median of 19 months in the TT/TG group, and 20 months in the GG group.
“MUC5B rs35705950 genotype does not seem to affect response to antifibrotic treatment in patients with IPF,” but “carriage of the mutant T allele is associated with longer survival in IPF patients on antifibrotic treatment,” the team concluded.
How the T allele is linked to better survival, however, is still an unknown.
“Larger studies and genotyping of additional genes involved in disease pathogenesis [development] are needed to assess the role of genotype stratification in clinical trial design and in clinical decision making,” the researchers wrote.
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