S67 Evidence that telomere length is causal for idiopathic pulmonary fibrosis but not chronic obstructive pulmonary disease: a UK biobank mendelian randomisation study

Introduction and objectives

Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease that accounts for 1% of UK deaths. Causal genes have been found accounting for about 30% of familial cases of pulmonary fibrosis and the majority relate to telomere maintenance. However, no evidence of causality in the idiopathic form of the disease has yet been found. Prematurely shortened leukocyte telomere length (LTL) has been associated with IPF and also Chronic Obstructive Pulmonary Disease (COPD), a disease with a similar demographic and symptomatology. Studies have shown age adjusted LTL values of 0.85 ± 0.60 vs 1.15 ± 0.6, p=0.0001 for IPF¹ and 0.68 ± 0.25 vs. 0.88 ± 0.52 (smoking controls), p = 0.003 for COPD.² We sought to investigate causality in IPF using Mendelian randomisation (MR) with UK Biobank data. To our knowledge, this is the first genetic study of this IPF cohort and the first application of MR to investigate causality in IPF. We hypothesised that prematurely shortened telomeres are causal in IPF but not in COPD.

Methods

We performed one- and two-sample MR in the UK Biobank data. This study had 1,133 IPF cases (defined by ICD10 code J84.1), 11,413 COPD cases and 378,575 controls, all of European ancestry. Seven variants previously associated with telomere length were used in the MR analysis. Pleiotropy was explored using MR approaches including MR-Egger and Median MR.

Results

A genetically instrumented one unit LTL shorter telomere length was associated with higher odds of IPF (OR 4.19 [95%CI: 2.33–7.55], P=0.0031). Similar results were found in males and females separately. Despite being an age-related lung disease with similar symptoms, there was no evidence that telomere length caused COPD.

Conclusions

Prematurely shortened telomeres have a likely causal effect in IPF. This enables a greater focus on telomere-related diagnostics, treatments and the search for a cure. Safe telomere activation therapy is being explored in the cardiology field, amongst others, using transient delivery of telomerase and there are also accessible therapies that show improved telomere length. Such approaches warrant investigation in IPF.

References

Dai, J., et al. Respirology, 2015. Rode, L., et al. Thorax, 2013.