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

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.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.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=2.19×10−12. 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).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.