Evidence that Telomere Length is Causal for Idiopathic Pulmonary Fibrosis but not Chronic Obstructive Pulmonary Disease: A Mendelian Randomisation Study

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in ~30% of cases, and a majority relate to telomere maintenance. Prematurely shortened leukocyte telomere length has also been associated with IPF, as well as chronic obstructive pulmonary disease (COPD), a disease with a similar demographic and shared risk factors. Using Mendelian randomisation (MR), our study aimed to determine whether short telomeres cause IPF or COPD. Methods: We performed an MR study for telomere length causality in IPF and COPD with up to 1,369 IPF cases, 14,103 COPD cases and 435,866 controls of European ancestry in UK Biobank. Initial studies using polygenic risk scores followed by two-sample MR analyses were carried out using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort of 2,668 IPF cases and 8,591 controls and a COPD cohort of 15,256 cases and 47,936 controls. Findings: Meta-analysis of the two-sample MR results provided evidence that shorter telomeres cause IPF, with a genetically instrumented one standard deviation shorter telomere length associated with 5.81 higher odds of IPF ([95% CI: 3.56-9.50], P=2.19x10-12. Despite being an age-related lung disease with overlapping risk, there was no evidence that telomere length caused COPD (OR 1.07, [95% CI 0.90-1.27], P = 0.46). Interpretation: Cellular senescence is hypothesised as a major driving force in both IPF and COPD; telomere shortening may be a contributory factor in IPF, suggesting divergent mechanisms in COPD. This enables greater focus in telomere-related diagnostics, treatments and the search for a cure in IPF. Therapies manifesting improvements in telomere length, including safe telomere activation therapy, may warrant investigation.

The Role of Herpes Viruses in Pulmonary Fibrosis

“…Recent evidence also supports a causal role for prematurely short telomeres in idiopathic PF. One study showed very short telomere lengths, similar in length to those found in patients with familial PF, in biopsies from the lungs of 15 of 28 IPF patients (10) and our team reported results inferring a causal effect of short telomeres in IPF using the statistical method of Mendelian randomization in large cohorts with genetic data (11). Studies in mouse models have shown that it is the AEC2 that are key to the short telomeric cause of lung remodeling and fibrosis (98) with dysfunctional chromosomal replication leading to cellular senescence and triggering the pro-fibrotic senescence-associated secretory phenotype (SASP) (99).…”

“…Animal studies clearly show that herpes virus-associated changes occur prior to onset of clinical features and in some cases that early treatment provides more greater benefit than later (81). For this reason, it will be all the more important to identify and diagnose people in the early stages of PF and to conduct trials at this time, rather than at symptomatic presentation, which is likely to represent a more treatment-resistant "end-stage" situation (11,121,122).…”

“…For Idiopathic PF (IPF), the most common form of PF, overall mortality is high with median survival of 3 years from diagnosis (8). Familial PF (FPF) has an established association with telomere maintenance (9) and evidence for a causal role for short telomeres in IPF is also growing (10,11). Many groups report increased prevalence of herpes virus in IPF, FPF and animal models of PF (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) although this is not a universal finding (26)(27)(28)(29)(30).…”

Airway Telomere Length in Lung Transplant Recipients

“…In comparison, recipient telomere length has consistently been shown to alter post-transplant outcomes, particularly in those with very short telomeres (20). A significant proportion of idiopathic pulmonary fibrosis is attributable to telomere related gene mutations (21)(22)(23)(24). Patients with pulmonary fibrosis related to such mutations, with extreme telomere shortening, may be more prevalent in the transplant population, owing to their earlier age of onset and worse prognosis.…”

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

“…Consistent with a role for telomere dysfunction in driving PF, AT2 cells in sporadic PF express hallmarks of senescence and have shorter telomeres in fibrotic regions than those in non-fibrotic regions (Disayabutr et al, 2016;Kropski et al, 2015;Snetselaar et al, 2017). Additionally, two human Mendelian randomization studies argue that short telomeres are a cause of PF (Duckworth et al, 2020;Telomeres Mendelian Randomization Collaboration et al, 2017). Murine studies also argue that telomere dysfunction and senescence in AT2 cells can drive PF (Naikawadi et al, 2016;Povedano et al, 2015;Yao et al, 2020).…”