A Causal Atlas on Comorbidities in Idiopathic Pulmonary Fibrosis: A Bidirectional Mendelian Randomization Study

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a high burden of both pulmonary and extrapulmonary comorbidities.

Research question: Do these comorbidities have causal relationships with IPF?

Study design and methods: We searched PubMed to pinpoint possible IPF-related comorbid conditions. Bidirectional Mendelian randomization (MR) was performed using summary statistics from the largest genome-wide association studies for these diseases to date in a two-sample setting. Findings were verified using multiple MR approaches under different model assumptions, replication datasets for IPF, and secondary phenotypes.

Results: A total of 22 comorbidities with genetic data available were included. Bidirectional MR analyses showed convincing evidence for two comorbidities and suggestive evidence for four comorbidities. Gastroesophageal reflux disease, VTE, and hypothyroidism were associated causally with an increased risk of IPF, whereas COPD was associated causally with a decreased risk of IPF. For the reverse direction, IPF showed causal associations with a higher risk of lung cancer, but a reduced risk of hypertension. Follow-up analyses of pulmonary function parameters and BP measures supported the causal effect of COPD on IPF and the causal effect of IPF on hypertension.

Interpretation: The present study suggested the causal associations between IPF and certain comorbidities from a genetic perspective. Further research is needed to understand the mechanisms of these associations.

Keywords: Mendelian randomization; causality; comorbidities; idiopathic pulmonary fibrosis.