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. 2025 Dec;20(1):2521622.
doi: 10.1080/15592294.2025.2521622. Epub 2025 Jun 19.

DNA methylation and bronchiectasis: a Mendelian randomization analysis to investigate causal link and therapeutic target

Jiangyue Qin  1   2 , Bi Ran  2 , Lian Liu  2 , Ping Li  2 , Zhenni Chen  3 , Diandian Li  2 , Yongchun Shen  2 , Fuqiang Wen  2
Affiliations

DNA methylation and bronchiectasis: a Mendelian randomization analysis to investigate causal link and therapeutic target

Jiangyue Qin et al. Epigenetics. 2025 Dec.

Abstract

This study aims to discover drug targeted genes and explore the potential epigenetics mechanisms in bronchiectasis. Cis-expression quantitative trait locus (eQTL) was obtained as exposure, and bronchiectasis from the FinnGen cohort was used as outcome. Mendelian Randomization (MR) was performed to identify therapeutic targets associated with bronchiectasis. Colocalization and summary-data-based MR (SMR) analyses were carried out to further confirm the causal roles of candidate genes in bronchiectasis. The value of these drug targets was validated via drug prediction and molecular docking. Finally, we used mediation analysis to identify the DNA methylation QTLs to bronchiectasis mediated by candidate genes. Ten drug targets were significantly associated with bronchiectasis. Strong evidence for the colocalization of ACVR2A and VRK2 with bronchiectasis was found (PP.H4 > 0.75). SMR analysis revealed that higher expressions of DDR1 and VRK2 were linked to a higher risk of bronchiectasis, and higher expressions of SCD5, TNFRSF4 and XCL2 were linked to a lower risk of bronchiectasis. Finally, mediation analysis revealed potential causality effect of the DNA methylation site cg21568453 to bronchiectasis risk via VRK2. The increased expression of VRK2 regulated by DNA methylation at cg21568453 may promote the occurrence of bronchiectasis.

Keywords: Bronchiectasis; DNA methylation; Mendelian randomization; VRK2; druggable genes.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Overview of the study design.
Figure 2.
Figure 2.
Forest plot of 10 significant genes related to bronchiectasis from blood.
Figure 3.
Figure 3.
Results of (a) GO and (b) KEGG enrichment for 10 genes.
Figure 4.
Figure 4.
Molecular docking results of VRK2 and the top five drugs. (a) WZ3105, (b) Flavopiridol, (c) Bosutinib, (d) Phenol and (e) SKI-606 Kinome Scan.
Figure 5.
Figure 5.
The VRK2 mediated the causal effect of cg21568453 on bronchiectasis.
See this image and copyright information in PMC

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