Abstract
Metabolic disorders are a significant feature of fibrotic diseases. Nevertheless, the lack of sufficient proof regarding the cause-and-effect association between circulating metabolites and the promotion or prevention of idiopathic pulmonary fibrosis (IPF) persists. To assess the causal association between IPF and genetic proxies of 486 blood metabolites, a dual sample Mendelian randomization (MR) analysis was performed. Therefore, the two-sample MR technique and genome-wide association study data were employed to assess the association between 486 serum metabolites and IPF. To produce the primary outcomes, the inverse variance weighted (IVW) technique was applied, while to assess the stability and dependability of the outcomes, sensitivity analysis using MR-Egger analysis was performed. Additionally, weighted median, Cochran's Q-test, Egger intercept test and the leave-one-out method were used. The results of the present study revealed a total of 21 metabolites in blood circulation that could affect the risk of IPF (P(IVW)<0.05). Among them, 10 compounds were already known, namely cotinine [odds ratio (OR)=1.206; 95% confidence interval (CI), 1.002-1.452; P=0.047], hypoxanthine (OR=0.225; 95% CI, 0.056-0.899; P=0.034), aspartyl phenylalanine (OR=4.309; 95% CI, 1.084-17.131; P=0.038), acetyl-carnitine (OR=5.767; 95% CI, 1.398-23.789; P=0.015), 2-aminobutyrate (OR=0.155; 95% CI, 0.033-0.713; P=0.016), Docosapentaenoic acid (PubChem ID: 5497182; OR=0.214; 95% CI, 0.055-0.833; P=0.026), octanoyl-carnitine (PubChem ID: 177508; OR=3.398; 95% CI, 1.179-9.794; P=0.023), alpha-hydroxy-isovalerate (PubChem ID: 857803-94-2; OR=0.324; 95% CI, 0.112-0.931; P=0.036), 1,7-dimethylurate (PubChem ID: 91611; OR=0.401; 95% CI, 0.172-0.931; P=0.033) and 1-linoleoyl-glycerophosphocholine (PubChem ID: 657272; OR=6.559; 95% CI, 1.060-40.557; P=0.043). Additionally, the study also identified 11 currently unknown chemical structures. The results of Cochran's Q-test indicated that there was no significant heterogeneity, while MR-Egger's intercept analysis verified the lack of horizontal pleiotropy. The retention of one method for plotting also supported the reliability of the MR analysis. Overall, the results of the current study supported the cause-and-effect association between IPF and 21 blood metabolites, including 10 with already known chemical composition and 11 which are still awaiting determination. These findings could provide novel insights for the further investigation of the mechanism underlying the development of IPF.