Plasma genome-wide mendelian randomization identifies potentially causal genes in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with a very poor prognosis. Existing drugs for the treatment of IPF are still insufficient. Therefore, there is still a need to explore new drug targets for preventing and treating IPF.

We included quantitative trait loci (QTL) for genes, DNA methylation, and proteins in plasma, as well as the summary statistics for IPF. Genetic variants located within 500 kb of the gene and strongly associated with plasma exposure were used as instrumental variables. The causal association between plasma exposures and IPF was primarily estimated using summary-data-based Mendelian randomization (SMR) analysis. Five other MR methods and sensitivity analyses were employed to validate the SMR results. Bayesian tests for colocalization between QTL and IPF risk loci further strengthen the MR results.

We identified three genes and five DNA methylation sites causally associated with IPF by SMR analysis, validation of MR analysis, sensitivity analysis, and colocalization analysis. BTRC and LINC01252 were negatively associated with IPF risk (OR: 0.30, 95% CI: 0.17-0.54, FDR_SMR = 0.029; OR: 0.85, 95% CI: 0.78-0.92, FDR_SMR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64-4.12, FDR_SMR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08-1.24, FDR_SMR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12-1.36, FDR_SMR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98-5.08, FDR_SMR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10-1.30, FDR_SMR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11-0.45, FDR_SMR = 0.013) was negatively correlated with the risk of IPF.

This study demonstrated that genetically determined plasma levels of the BTRC, RIPK4, and LINC01252 genes, as well as methylation levels of cg00045227 (OR8U8), cg00577578 (GBAP1), cg07163735 (MAPT), cg14222479 (ARPM1), and cg19263494 (PMF1), have causal influences on the risk of IPF.