Dressen A, et al. - Authors evaluated whether or not rare protein-altering variants in genes regulating telomere length were enriched in patients with idiopathic pulmonary fibrosis (IPF) homozygous for the non-risk alleles at rs35705950. In patients with IPF, rare protein-altering variants in TERT, PARN, TERC, and RTEL1 are enriched vs controls, and, in the case of TERT, particularly in individuals without a risk allele at the rs35705950 locus. Findings suggested a contribution of multiple genetic factors in sporadic IPF, which might implicate distinct mechanisms of pathogenesis and disease progression.

Methods

• Between Nov 1, 2014, and Nov 1, 2016, researchers evaluated the blood samples from patients aged 40 years or older and of European ancestry with sporadic IPF from three international phase 3 clinical trials (INSPIRE, CAPACITY, ASCEND), one phase 2 study (RIFF), and US-based observational studies (Vanderbilt Clinical Interstitial Lung Disease Registry and the UCSF Interstitial Lung Disease Clinic registry cohorts) at the Broad Institute (Cambridge, MA, USA) and Human Longevity (San Diego, CA, USA).
• They also evaluated the blood samples from non-IPF controls in several clinical trials.
• They performed whole-genome sequencing to evaluate telomere length and identify rare protein-altering variants, stratified by rs35705950 genotype.
• Experts also ascertained the rare functional variation in TERT exons and compared telomere length and disease progression across genotypes.

Results

• As per data, samples from 1510 patients with IPF and 1874 non-IPF controls were assessed.
• A rare protein-altering variant in TERT was seen in 30 (3%) of 1046 patients with an rs35705950 risk allele vs 34 (7%) of 464 non-risk allele carriers (odds ratio 0·40 [95% CI 0·24–0·66], p=0·00039).
• Enrichment of rare protein-altering variants in PARN and RTEL1, and rare variation in TERT in patients with IPF compared with controls were identified on subsequent analyses.
• In order to provide a more accurate estimation of rare variant frequency in these four loci, and to calculate telomere length, the study population was expanded.
• Findings suggested that the proportion of patients with at least 1 rare variant inTERT, PARN, TERC, or RTEL1 was higher in patients with IPF than in controls (149 [9%] of 1739 patients vs 205 [2%] of 8645 controls, p=2·44 × 10^-8).
• In patients with IPF who had a variant in any of the 4 identified telomerase component genes, experts identified telomeres that were 3·69–16·10% shorter than patients without a variant in any of the 4 genes.
• The former group of patients had an earlier mean age of disease onset than patients without one or more variants (65·1 years [SD 7·8] vs 67·1 years [7·9], p=0·004).
• In the placebo arms of clinical trials, they noted a significant association between the shorter telomeres with faster disease progression (1·7% predicted forced vital capacity per kb per year, p=0·002).
• They noted the treatment benefit of pirfenidone regardless of telomere length (p=4·24 × 10^-8 for telomere length lower than the median, p=0·0044 for telomere length greater than the median).