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ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Reproduction
Volume 15 - 2024 |
doi: 10.3389/fendo.2024.1416384
Mendelian randomization analysis and validation supports MEGF9 and MLLT11 as potential targets for the treatment of varicocele and male infertility
Provisionally accepted- 1 Zhongda Hospital, Southeast University, Nanjing, China
- 2 Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, China
- 3 School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
Objective:A growing body of research suggests a link between varicocele and male infertility (MI). However, current evidence is mainly based on retrospective studies, which are prone to interference from confounding factors and cannot establish causal relationships. Mendelian randomization (MR) studies on the causal relationship between varicocele and MI are very limited. Therefore, this study conducted a two-sample MR study to elucidate the causal effect between the two. Methods: Download the data set GSE216907 from the GEO database, and use R software to screen differential genes in normal and varicocele tissue samples. The drug targets of Bu Shen Huo Xue Prescription (BSHXP) were derived from the Herb database. All genetic datasets were obtained using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. MR analysis was performed using MR Egger, weighted median (WM) and inverse variance weighted (IVW) to assess the causal relationship between exposure and outcome and to validate the findings by comprehensively evaluating the effects of pleiotropic effects and outliers. The renal vein constriction method was used to establish a pathological model of varicocele infertility. Results: MEGF9 and MLLT11, and were verified by molecular docking. MR analysis showed that MEGF9 was positively associated with MI (MR Egger, OR: 1.639, 95% CI: 1.124-2.391, P = 0.024; WM, OR: 1.235, 95% CI: 1.003-1.521, P = 0.047). MEGF9 is also positively associated with MI (IVW, OR: 1.35, 95% CI: 1.069-1.705, P = 0.012). Sensitivity analysis showed no heterogeneity and horizontal pleiotropy. The expression of MEGF9 and MLLT11 increased in the varicocele model group, while the expression decreased after treatment with low, medium, and high doses of BSHXP. In addition, the sperm number, motility, morphology, and fertility of rats in the model group were significantly lower than those in the control group (P<0.05). After BSHXP treatment, all indicators were significantly better than those of the model group (P<0.05). Conclusion: This study indirectly supports that varicocele causes MI. BSHXP inhibiting MEGF9 and MLLT11 may become a potential therapeutic target for alleviating varicocele and MI.
Keywords: Varicocele, male infertility, Genetic causal effect, Mendelian Randomization Analysis, Bu Shen Huo Xue Prescription
Received: 12 Apr 2024; Accepted: 03 Sep 2024.
Copyright: © 2024 Cai, Sun, Deng, Jin, Zhao, Xing, Liu and Jin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Baofang Jin, Zhongda Hospital, Southeast University, Nanjing, China
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