Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin
Abstract This study employed a trans-ethnic two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between membranous nephropathy (MN) and peripheral artery disease (PAD). In European populations, MN exhibited a significant positive causal effect on PAD (discovery: O...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-02626-3 |
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| author | Juhong Pan Xingyue Huang Yueying Chen Nan Jiang Yuxin Guo Shiyuan Zhou Yao Zhang Bo Hu Qing Deng Qing Zhou |
| author_facet | Juhong Pan Xingyue Huang Yueying Chen Nan Jiang Yuxin Guo Shiyuan Zhou Yao Zhang Bo Hu Qing Deng Qing Zhou |
| author_sort | Juhong Pan |
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| description | Abstract This study employed a trans-ethnic two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between membranous nephropathy (MN) and peripheral artery disease (PAD). In European populations, MN exhibited a significant positive causal effect on PAD (discovery: OR = 1.040, P = 0.028; validation: OR = 1.028, P = 0.031), whereas no such association was observed in East Asians (P > 0.05). A two-step mediation analysis identified several proteins influenced by MN, including thrombomodulin (TM) (β = 0.031, P = 0.001), macrophage colony-stimulating factor 1 (MCSF1) (β = 0.239, P = 0.015), stem cell factor (SCF) (β = 0.028, P = 0.002), and tissue factor (TF) (β = 0.031, P = 0.001), while MN negatively affected interleukin-1β (IL-1β) (β=-0.049, P = 0.015) and hepatocyte growth factor (HGF) (β=-0.027, P = 0.005). Multivariable MR analysis confirmed that only TM had an independent positive causal effect on PAD (β = 0.225, P < 0.001), and mediation analysis further validated TM as a significant mediator in the MN-to-PAD pathway (Z = 2.823, P = 0.048). Sensitivity analyses detected no significant pleiotropy or heterogeneity, supporting the robustness of our findings. This study highlights crucial ethnic differences in MN-associated PAD risk and underscores the importance of population-specific research. TM may serve as a potential therapeutic target for PAD prevention in MN patients, particularly those of European ancestry, providing novel insights into kidney-vascular disease mechanisms. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-7773a53fbfa64504ba0a10ebc6d2bfe92025-08-20T03:48:15ZengNature PortfolioScientific Reports2045-23222025-05-0115111210.1038/s41598-025-02626-3Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulinJuhong Pan0Xingyue Huang1Yueying Chen2Nan Jiang3Yuxin Guo4Shiyuan Zhou5Yao Zhang6Bo Hu7Qing Deng8Qing Zhou9Department of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityDepartment of Ultrasound Imaging, Renmin Hospital of Wuhan UniversityAbstract This study employed a trans-ethnic two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between membranous nephropathy (MN) and peripheral artery disease (PAD). In European populations, MN exhibited a significant positive causal effect on PAD (discovery: OR = 1.040, P = 0.028; validation: OR = 1.028, P = 0.031), whereas no such association was observed in East Asians (P > 0.05). A two-step mediation analysis identified several proteins influenced by MN, including thrombomodulin (TM) (β = 0.031, P = 0.001), macrophage colony-stimulating factor 1 (MCSF1) (β = 0.239, P = 0.015), stem cell factor (SCF) (β = 0.028, P = 0.002), and tissue factor (TF) (β = 0.031, P = 0.001), while MN negatively affected interleukin-1β (IL-1β) (β=-0.049, P = 0.015) and hepatocyte growth factor (HGF) (β=-0.027, P = 0.005). Multivariable MR analysis confirmed that only TM had an independent positive causal effect on PAD (β = 0.225, P < 0.001), and mediation analysis further validated TM as a significant mediator in the MN-to-PAD pathway (Z = 2.823, P = 0.048). Sensitivity analyses detected no significant pleiotropy or heterogeneity, supporting the robustness of our findings. This study highlights crucial ethnic differences in MN-associated PAD risk and underscores the importance of population-specific research. TM may serve as a potential therapeutic target for PAD prevention in MN patients, particularly those of European ancestry, providing novel insights into kidney-vascular disease mechanisms.https://doi.org/10.1038/s41598-025-02626-3Peripheral artery diseaseMembranous nephropathyThrombomodulinMediationMendelian randomization |
| spellingShingle | Juhong Pan Xingyue Huang Yueying Chen Nan Jiang Yuxin Guo Shiyuan Zhou Yao Zhang Bo Hu Qing Deng Qing Zhou Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin Scientific Reports Peripheral artery disease Membranous nephropathy Thrombomodulin Mediation Mendelian randomization |
| title | Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin |
| title_full | Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin |
| title_fullStr | Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin |
| title_full_unstemmed | Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin |
| title_short | Trans-ethnic Mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin |
| title_sort | trans ethnic mendelian randomization analysis of membranous nephropathy and peripheral artery disease with mediating effects of thrombomodulin |
| topic | Peripheral artery disease Membranous nephropathy Thrombomodulin Mediation Mendelian randomization |
| url | https://doi.org/10.1038/s41598-025-02626-3 |
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