MUC5B Genetic Variants, Short Telomeres Linked to Greater Lung Damage, Poorer Survival in Chinese Patients, Study Shows

MUC5B genetic variants and shorter telomeres — or chromosome endings — are risk factors associated with greater lung damage and poorer survival in Chinese patients with idiopathic pulmonary fibrosis (IPF), a study has revealed.

The study, “The relationship between MUC5B promoter, TERT polymorphisms and telomere lengths with radiographic extent and survival in a Chinese IPF cohort,” was published in the journal Nature Scientific Reports.

While a better understanding of the underlying processes and risk factors that lead to IPF are urgently needed, several genetic factors have been associated with the disease.

Research points to genetic alterations, or polymorphisms, in genes that provide instructions for making telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), as possible contributors to the development of pulmonary fibrosis. In fact, according to the the National Institutes of Health, 15% of all cases of IPF are related to mutations in these genes.

TERC and TERT are responsible for making components of telomerase, an enzyme that extends “DNA caps” at the end of chromosomes called telomeres. These structures are very important in protecting the genome from wearing down and cells from entering an aging-like process.

Maintaining telomere length is important because when telomeres get too short, cells irreversibly stop dividing and acquire features of aged cells.

In fact, telomere shortening has been linked to increased susceptibility and lower survival in IPF patients. For this reason, scientists report that IPF is the most frequent manifestation of telomerase-associated disease.

Prior studies have also linked variations at the mucin 5B gene (MUC5B) to the risk of IPF and poor prognosis of patients. However, most of these studies were conducted in Western countries or looked at genetic variants that are rare in Asian populations.

Recognizing the need to address risk factors in Asian patients, researchers investigated the association between genetic variations in MUC5B and TERT, as well as changes in telomere length, and the extent of lung fibrosis and survival in a group of Chinese IPF patients.

In total, 79 patients (86.08% males; mean age of 64.19 years) and 200 age- and sex-matched healthy controls were enrolled in the study at the Nanjing Drum Hospital in China. The mean follow-up time was 30.36 months.

Participants were screened for five small genetic variations (single-nucleotide polymorphisms, or SNPs) — rs35705950 and rs868903 in MUC5B, rs2736100 and rs2853676 in TERT, and rs1881984 in TERC. Their telomere length was also determined using blood samples.

Variations within each participant were compared with the extent of radiographic lung fibrosis seen on chest high-resolution computed tomography scans (HRCT), and with survival data. The extent of lung fibrosis was specifically measured by scoring honeycombing (clustered air spaces), an abnormal HRCT finding characteristic of IPF, used by doctors to definitively diagnose the disease.

HRCT results showed that a minority of patients (13 patients; 16.46%) had mild honeycombing (in less than 10% of the lung), while 34 patients (43.04%) had moderate honeycombing (10–50%), and 32 patients (40.51%) had severe honeycombing (more than 50% of the lung).

Patients who carried one of two genetic variants — CT or CC at the MUC5B promoter rs868903 — or those who had shorter telomeres had more extensive honeycombing on chest scans.

After adjusting for age, sex, and smoking status, the CT/CC variants in MUC5B also emerged as a genetic risk factor for poorer survival, linked to a higher risk of death over time in IPF patients. Of note, 38 (35.44%) of the total patients analyzed died during the follow-up period.

According to the team, this is the first study to find that MUC5B promoter variations and telomere size are associated with radiological features, and that MUC5B variations “were a predictive factor for the prognosis in a Chinese IPF cohort.”

“Further investigations are needed to determine exactly potential role of MUC5B gene in the pathogenesis of IPF, and the regulation mechanisms of telomere shortening,” they added.