甲氨蝶呤对帕金森病保护作用的遗传证据：一项孟德尔随机化与共定位研究

Genetic evidence of methotrexate's protective role against Parkinson's disease: A Mendelian randomization and co-localization study.

作者信息

Zou Fang-Shu, Liu Min-Ying, Ma Xiao-Na, Shi Mei-Feng, Feng Wei, Xu Qiang

机构信息

State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China.

出版信息

Int Immunopharmacol. 2025 Apr 16;152:114386. doi: 10.1016/j.intimp.2025.114386. Epub 2025 Mar 9.

DOI:10.1016/j.intimp.2025.114386

PMID:40064058

Abstract

BACKGROUND

Recent research has indicated a possible link between the use of methotrexate (MTX) and a heightened risk of developing Parkinson's disease (PD). Nevertheless, the causal relationship between MTX and PD continues to be unclear. This study aimed to explore the potential causal impact of MTX use on the risk of PD by employing two-sample Mendelian randomization (MR) alongside co-localization (COLOC) analysis.

OBJECTIVE

The objective of this research is to explore the potential causal relationship between the use of methotrexate and the likelihood of developing Parkinson's disease, employing a two-sample Mendelian randomization (TSMR) methodology.

METHODS

Separate datasets concerning the genetic tools associated with MTX and PD were acquired from the Genome-Wide Association Study (GWAS) database. A series of MR-related statistical analyses were executed, such as inverse variance weighting (IVW), weighted median (WM 1), weighted mode (WM 2), and MR-Egger regression techniques. Furthermore, we carried out co-localization analyses utilizing the GWAS summary statistics for both MTX and PD in order to comprehensively evaluate the causal relationship between MTX and the risk of developing PD.

RESULTS

The MR analysis revealed a positive causal connection between methotrexate (MTX) and a decreased likelihood of developing Parkinson's disease (PD). In particular, the IVW method showed a negative association between MTX use and PD incidence, indicating that MTX is linked to a lower risk of PD (OR = 4.78E-11, 95 % CI = 1.06E-19 to 2.16E-02, p = 1.94E-08). Similar findings were acquired through the WM 1, WM 2, and MR-Egger methodologies. Additionally, COLOC analysis indicated a shared genetic variant between MTX and PD at a specific locus.

CONCLUSION

The results from this joint MR and COLOC research indicate a possible causal link between the use of methotrexate and the likelihood of developing Parkinson's disease. Nonetheless, further research and confirmation of these results, as well as an examination of potential mechanisms, are necessary.

摘要

背景

近期研究表明，使用甲氨蝶呤（MTX）与患帕金森病（PD）风险增加之间可能存在联系。然而，MTX与PD之间的因果关系仍不明确。本研究旨在通过采用两样本孟德尔随机化（MR）和共定位（COLOC）分析，探讨使用MTX对PD风险的潜在因果影响。

目的

本研究的目的是采用两样本孟德尔随机化（TSMR）方法，探讨使用甲氨蝶呤与患帕金森病可能性之间的潜在因果关系。

方法

从全基因组关联研究（GWAS）数据库中获取有关与MTX和PD相关的遗传工具的单独数据集。执行了一系列与MR相关的统计分析，如逆方差加权（IVW）、加权中位数（WM 1）、加权众数（WM 2）和MR-Egger回归技术。此外，我们利用MTX和PD的GWAS汇总统计数据进行共定位分析，以全面评估MTX与患PD风险之间的因果关系。

结果

MR分析显示甲氨蝶呤（MTX）与患帕金森病（PD）可能性降低之间存在正向因果联系。特别是，IVW方法显示MTX使用与PD发病率之间存在负相关，表明MTX与较低的PD风险相关（OR = 4.78E-11，95% CI = 1.06E-19至2.16E-02，p = 1.94E-08）。通过WM 1、WM 2和MR-Egger方法也获得了类似的结果。此外，COLOC分析表明MTX和PD在一个特定位点存在共同的遗传变异。