Homocysteine and risk of interstitial lung disease: A mendelian randomization approach to causal inference

Homocysteine (Hcy) has been implicated in inflammatory, oxidative stress (OS), and endoplasmic reticulum (ER) stress mechanisms, which are hypothesized to contribute to the pathogenesis of interstitial lung disease (ILD). Given the paucity of evidence regarding Hcy's role in ILD, a two-sample Mendelian randomization study was performed to investigate the causal association between Hcy and ILD.

We sourced data for total plasma Hcy from genome-wide association studies (GWAS) involving 44,147 European individuals. Data for ILD, idiopathic pulmonary fibrosis (IPF), IPF-related respiratory insufficiency, and systemic autoimmune disease-associated IPF were derived from the FinnGen consortium. To evaluate the causal association of reduced total plasma Hcy with ILD and related conditions, a range of Mendelian randomization (MR) analytical techniques were utilized to analyze the data. The results are reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). We conducted sensitivity analyses through leave-one-out procedures and Radial MR plots.

Our IVW estimates suggested that total plasma Hcy had a potential causal association with IPF (OR=0.649, 95%CI: 0.495-0.851), indicating that along with total plasma Hcy depressed 1 µmol/L, odds of IPF decreased 0.351. Although it seemed that decreased total plasma Hcy level is associated with lower odds of IPF-related respiratory insufficiency (OR=0.672, 95%CI: 0.489-0.924), due to the existence of horizontal pleiotropy, this causal association was not robust. In addition, MR leave-one-out and Radial MR sensitivity analyses showed there is no outlier among the selected IVs that could affect the potential causal relationship between Hcy and IPF.

The levels of total plasma Hcy may bear a significant association with the risk of developing IPF, a specific form of ILD. However, to definitively establish a causal relationship between elevated Hcy levels and the pathogenesis of ILD, additional well-controlled, prospective studies are indispensable.