Mendelian randomization revealed a one-way causal association between increased Isovalerylcarnitine (C5) levels and the risk of idiopathic pulmonary fibrosis.

There have been multiple observational studies that have established a link between metabolite levels in the body and idiopathic pulmonary fibrosis (IPF), specifically focusing on metabolites derived from fatty acids. However, a complete understanding of the precise molecular and biological factors, as well as the causality between them, remains elusive. The main objective of our study was to evaluate the potential causal relationship between blood metabolites and IPF by using Mendelian randomization (MR). To achieve this goal, we utilized the most comprehensive genome-wide association study to date, which identified genetic variants associated with blood metabolites (1091 blood metabolites and 309 metabolite ratios). Summary statistics of IPF were collected from Finngen R8 (1812 IPF patients and 338,784 controls), inverse variance weighted method (IVW) is used as the main method in determining causality. Isovalerylcarnitine (C5) levels (OR = 1.2435, 95% CI: 1.0494-1.4736, Pval = .0119) was found significantly related to higher risk of IPF. There was no significant heterogeneity in our study (IVW method: Pval = .132; MR-Egger method: Pval = .105) and horizontal pleiotropy (β = -0.027; SE = 0.0337; Pval = .4310). The sensitivity analysis did not reveal any potential abnormal drivers (0.1 < All < 0.3). Two-sample MR method demonstrated the causal relationship between blood metabolites and IPF, and further studies found that Isovalerylcarnitine (C5) levels, as a potential biological risk factor for IPF, may provide a new target for the treatment of IPF.