Assessing causal relationships between diabetes mellitus and idiopathic pulmonary fibrosis: a Mendelian randomisation study

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung scarring. There is a known association between diabetes mellitus (DM) and IPF, but it is unclear whether a causal relationship exists between these traits. Objectives The objectives of this study are to examine causal relationships among DM, diabetes-associated traits and IPF using a Mendelian randomisation approach. Methods Two-sample MR approaches, including bidirectional inverse-variance weighted random effects and routine sensitivity models, used genetic variants identified from genome-wide association studies for type 1 diabetes (T1D), type 2 diabetes (T2D), glycated haemoglobin level (HbA1c), fasting insulin level and body mass index (BMI) to assess for causal effects of these traits on IPF. Further analyses using pleiotropy-robust and multivariable MR (MVMR) methods were additionally performed to account for trait complexity. Results Results did not suggest that either T1D (OR=1.00, 95% CI 0.93 to 1.07, p=0.90) or T2D (1.02, 0.93 to 1.11, p=0.69) are in the causal pathway of IPF. No effects were suggested of HbA1c (1.19, 0.63 to 2.22, p=0.59) or fasting insulin level (0.60, 0.31 to 1.15, p=0.12) on IPF, but potential effects of BMI on IPF were indicated (1.44, 1.12 to 1.85, p=4.00×10−3). Results were consistent in MVMR, although no independent effects of T2D (0.91, 0.68 to 1.21, p=0.51) or BMI (1.01, 0.94 to 1.09, p=0.82) on IPF were observed when modelled together. Conclusions This study suggests that DM and IPF are unlikely to be causally linked. This comorbid relationship may instead be driven by shared risk factors or treatment effects. Data are available upon reasonable request. Summary results for the GWAS of IPF susceptibility were requested through the collaborative genetic studies of idiopathic pulmonary fibrosis GitHub page: (). Summary data for all other GWAS studies were retrieved from GWAS catalog ().