Genetically predicted GLP-1R expression and idiopathic pulmonary fibrosis: A Mendelian randomization mediation study of JAKMIP3 and pulmonary function
- 1Department of Thoracic Surgery, The Affiliated LiHuiLi Hospital of Ningbo University, China
- 2The First Department of Breast Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, China
- 3Health Science Center, Ningbo University, China
Abstract
Objective: To 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.
Methods: We 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.
Results: Higher 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.
Conclusions: The 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.
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BibTeX
@article{liang2026genetically,
title = {{Genetically predicted GLP-1R expression and idiopathic pulmonary fibrosis: A Mendelian randomization mediation study of JAKMIP3 and pulmonary function}},
author = {Gaofeng Liang and Dongchen Tian and Keyun Zhu and Yingxi Li and Jing Zeng and Yan Shen and Zhaohui Chen and Yao Tian},
journal = {The Journal of International Medical Research},
year = {2026},
month = sep,
doi = {10.1177/03000605261488118},
url = {https://doi.org/10.1177/03000605261488118},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Genetically predicted GLP-1R expression and idiopathic pulmonary fibrosis: A Mendelian randomization mediation study of JAKMIP3 and pulmonary function
AU - Gaofeng Liang
AU - Dongchen Tian
AU - Keyun Zhu
AU - Yingxi Li
AU - Jing Zeng
AU - Yan Shen
AU - Zhaohui Chen
AU - Yao Tian
PY - 2026
DA - 2026/09/18
JO - The Journal of International Medical Research
DO - 10.1177/03000605261488118
UR - https://doi.org/10.1177/03000605261488118
AB - Objective: To 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. Methods: We 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. Results: Higher 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. Conclusions: The 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.
SN - 0300-0605
SN - 1473-2300
ER -