Study of the associations between short telomeres, sex hormones and pulmonary fibrosis

Abstract

Background Pulmonary fibrosis (PF) is an incurable fibrotic lung disease with limited treatment options and a high mortality. Evidence is growing that short telomeres cause both heritable and idiopathic pulmonary fibrosis (IPF). Based on survival data, we hypothesised that sex hormones are protective against premature telomere attrition and could influence PF disease onset and/or progression. Methods Associations between IPF, sex hormone concentrations and measured leukocyte telomere length (LTL) were examined for unrelated UK Biobank participants of European ancestry with a diagnosis of IPF (415 females, 718 males) against controls (204,321 females, 174,254 males). Polygenic risk scores were used to explore causality between sex hormone indices, LTL and disease. Findings Strong associations were found between IPF and LTL. For females, higher odds of having IPF was associated with early menopause and premature ovarian failure. Menopause age correlated positively with both age of IPF diagnosis and age of death. For males, IPF prevalence and stages of disease were associated with serum bioavailable testosterone concentrations. For both sexes, evidence of lower concentrations of sex hormones was associated with shorter LTL. Genetic analysis also inferred bi-directional causal links between sex hormone binding globulin concentration, which impacts free testosterone concentration, and LTL in males. Interpretation Our findings suggest that higher sex hormone concentrations protect against IPF onset and progression, possibly by slowing telomere shortening. Hormonal supplementation may delay or prevent disease onset for those with telomere-associated PF risk and improve disease prognosis. This warrants further exploration in a randomised controlled trial.

Competing Interest Statement

MAG has received support to attend conferences and professional fees from Roche and Boehringer-Ingelheim, outside of the submitted work.

Funding Statement

This work was supported in part by grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. KSR is supported by Cancer Research UK [grant number C18281/A29019]. JKP is supported by the UKRI Expanding Excellence in England award. JT is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK [SBF004\1079]. CJS is supported by MRC project grants (MR/V002538/1 and MR/S002626/1). This research has been conducted using the UK Biobank Resource (applications 9072 and 44046).

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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UK Biobank has ethical approval from the North West Centre for Research Ethics Committee (Application 11/NW/0382), which covers the UK. UK Biobank obtained informed consent from all participants. Full details can be found at https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics. The work in this manuscript was approved by UK Biobank (Applications 9072 and 44046).

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Data Availability

All data produced in the present work are contained in the manuscript

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