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

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-09 DOI:10.1016/j.intimp.2025.114386

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

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引用次数: 0

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.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.