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: 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.

Keywords: Mediation; Membranous nephropathy; Mendelian randomization; Peripheral artery disease; Thrombomodulin.

Fig. 1

Study overview. A, The phenotypes included in the overall MR analysis. B, The causal effects of MN on PAD in European and East Asian ancestries were analyzed using UVMR. When the results were significant, reverse MR was performed to identify the causal association of PAD on MN. C, Two-step MR was conducted to screen 10 potential mediators involved in the MN-PAD axis. The mediation effects and proportions for validated mediators were quantified. MN, Membranous nephropathy; PAD, Peripheral artery disease; MR, Mendelian randomization; UVMR, univariable Mendelian randomization; MVMR, multivariable Mendelian randomization; MMP12, Matrix metalloproteinase-12; TM, Thrombomodulin; TF, Tissue factor; MCSF1, Macrophage colony-stimulating factor 1; IL-1β, Interleukin-1 beta; CRP, C-reactive protein; CD4, T-cell surface glycoprotein CD4; BNGF, Beta-nerve growth factor; HGF, Hepatocyte growth factor; SCF, Stem cell factor. (Figure was partly created with Figdraw).

Fig. 2

Forest plot of univariable MR causal associations of MN on PAD. Different methods were used to obtain OR values and 95% confidence intervals. MN, Membranous nephropathy; PAD, Peripheral artery disease; dis, discovery; val, validation; CI confidence interval, OR odds ratio.

Fig. 3

Forest plot of univariable MR causal associations of MN on 10 candidate mediators. Different methods were used to obtain beta values and 95% confidence intervals. MMP12, Matrix metalloproteinase-12; TM, Thrombomodulin; TF, Tissue factor; MCSF1, Macrophage colony-stimulating factor 1; IL-1β, Interleukin-1 beta; CRP, C-reactive protein; CD4, T-cell surface glycoprotein CD4; BNGF, Beta-nerve growth factor; HGF, Hepatocyte growth factor; SCF, Stem cell factor; β effect size for the effect allele; FDR-P P value of False Discovery Rate.

Fig. 4

Selection process for significant mediators in the causal relationship of MN with PAD. MN, Membranous nephropathy; PAD, Peripheral artery diseaseMMP12, Matrix metalloproteinase-12; TM, Thrombomodulin; TF, Tissue factor; MCSF1, Macrophage colony-stimulating factor 1; IL-1β, Interleukin-1 beta; CRP, C-reactive protein; CD4, T-cell surface glycoprotein CD4; BNGF, Beta-nerve growth factor; HGF, Hepatocyte growth factor; SCF, Stem cell factor. The full MR estimates are shown in Table S6 and Table 2.