The causality between telomere length and chronic lung diseases: A Bidirectional Mendelian Randomization Analysis

Abstract

Background Previous studies have observed the abnormality in telomere biology and function during the process of chronic lung diseases (CLDs). However, whether alteration of telomere length (TL) causally facilitates the incidence of CLDs remains to be determined. Therefore, we here aim to estimate the causal effect of TL on the risk of CLDs using mendelian randomization (MR) analysis. Methods Single nucleotide polymorphisms (SNPs) strongly associated with TL and CLDs were selected as genetic variables from the genome-wide association studies (GWAS). A bidirectional two-sample MR analysis primarily based on inverse variance weighted (IVW) method was then conducted to infer the causality between TL and CLDs. Cochran’s Q test and MR-Egger regression analysis were performed to assess the heterogeneity and pleiotropy, and leave-one-out analysis was tested to determine the stability of MR results. Results The forward MR analysis indicated that among non-neoplastic CLDs, elevated TL was causally related to reduced risk of asthma (OR = 0.9986, 95%CI 0.9972–0.9999, P = 0.035), chronic obstructive pulmonary disease (COPD) (OR = 0.9987, 95%CI 0.9975–0.9999, P = 0.040), idiopathic pulmonary fibrosis (IPF) (OR = 0.9971, 95%CI 0.9961–0.9980, P < 0.001), and sarcoidosis (OR = 0.6820, 95%CI 0.5236–0.8884, P = 0.005). For neoplastic CLDs, increased TL genetically predicted higher risk of non-small cell lung cancer (OR = 1.8485, 95%CI 1.4074–2.4279, P < 0.001) and lung adenocarcinoma (OR = 1.9636, 95%CI 1.2275–3.1412, P = 0.005). However, there presented no significant causality between TL and pulmonary arterial hypertension, pneumoconiosis, small cell lung cancer and squamous cell lung cancer. Moreover, reverse MR analysis all showed no obvious causalities of CLDs with TL, except for sarcoidosis (OR = 0.9936, 95%CI 0.9887–0.9984, P = 0.010). Sensitivity analyses suggested the robustness of MR results with no horizonal pleiotropy despite of partial heterogeneity in reverse MR analysis. Conclusions Our study demonstrates that TL is causally associated with decreased risk of several non-neoplastic CLDs (asthma, COPD and IPF), whereas associated with increased risk of non-small cell lung cancer (especially adenocarcinoma). There’s mutual causality between TL attrition and sarcoidosis onset. This study comprehensively elucidated the causal associations between TL and CLDs, and might provide a promising target for the prevention of these CLDs.