ObjectiveTo evaluate the association between genetically predicted GLP-1R expression and idiopathic pulmonary fibrosis and to explore potential mediation through JAKMIP3 and pulmonary-function traits using Mendelian randomization.MethodsWe conducted a two-sample drug-target cis-Mendelian randomization study using Genotype-Tissue Expression lung cis-expression quantitative trait locus summary data as genetic proxies for GLP-1R expression and FinnGen R5 summary data (1028 cases and 196,986 controls; n = 198,014) for idiopathic pulmonary fibrosis. Type 2 diabetes mellitus served as a positive control, and a targeted panel of circulating molecular and pulmonary-function traits was evaluated using two-step Mendelian randomization. Primary estimates were obtained using inverse-variance weighting, with complementary estimators and sensitivity analyses. For the European-ancestry pulmonary function analyses, we used measured forced expiratory volume in 1 s (GCST90691840), forced vital capacity (GCST90691839), and peak expiratory flow (GCST90691841) genome-wide association studies, each including 383,471 participants.ResultsHigher genetically predicted GLP-1R expression was associated with a lower risk of idiopathic pulmonary fibrosis on inverse-variance weighted analysis (odds ratio = 0.740, 95% confidence interval: 0.632-0.866, p = 1.83 × 10-4). The positive-control analysis supported the biological coherence of the GLP1R expression proxy (type 2 diabetes mellitus, odds ratio = 0.630). JAKMIP3 was identified as a candidate circulating protein mediator, with a mediation proportion of 9.8%. In the European-ancestry pulmonary function analyses, forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow showed mediation proportions of 14.2%, 22.6%, and 11.8%, respectively, with the largest estimate observed for forced vital capacity.ConclusionsThe findings support an association between genetically predicted higher GLP-1R expression and lower risk of idiopathic pulmonary fibrosis and identify JAKMIP3 and pulmonary-function traits as candidate intermediates. These results provide a rationale for mechanistic and clinical studies evaluating glucagon-like peptide-1 receptor-related pathways in idiopathic pulmonary fibrosis.
