通过可用药基因的孟德尔随机化分析鉴定心房颤动的新治疗靶点。

IF 4.3

Experimental gerontology Pub Date : 2025-05-30 DOI:10.1016/j.exger.2025.112797

Yining Ding , Rumeng Chen , Zhiwei Zheng , Shuling Xu , Menghua Liu, Chunyan Hou, Sen Li

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引用次数: 0

摘要

背景：创新的治疗方法对于房颤（AF）的治疗至关重要，然而房颤特异性药物靶点的遗传支持仍然有限。方法：本孟德尔随机化（MR）研究采用顺式表达数量性状位点（cis- eqtl）来评估基因表达与AF之间的因果关系。在FinnGen中进行多次检测调整和验证，在UK Biobank中获得显著性后，进行共定位分析和蛋白质数量性状位点（pQTL）分析。结果：在UK Biobank中，65个基因的基因表达与房颤风险显著相关，其中15个基因在FinnGen中被重复。共定位分析确定了三个主要候选者：WDR1、ESR2和CXCL10，它们在逆方差加权（IVW）分析中具有显著相关性。ESR2与AF呈正相关(OR = 1.403；95 % CI: 1.200-1.640)，而WDR1 (OR = 0.800；95 % CI: 0.734-0.871)和CXCL10 (OR = 0.814；95 % CI: 0.738-0.897)呈负相关。由于缺乏ESR2和WDR1的pQTL数据，pQTL分析仅关注于CXCL10 (OR = 0.59；95 % ci: 0.43-0.82)。MR-Egger方法和加权中位数方法的结果与IVW分析的结果基本一致。结论：ESR2、WDR1和CXCL10有望成为AF治疗的靶点。

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Identification of novel therapeutic targets for atrial fibrillation through Mendelian randomization analysis of druggable genes

Background

Innovative therapeutic approaches are essential for treating atrial fibrillation (AF), yet genetic support for AF-specific drug targets remains limited.

Methods

This Mendelian randomization (MR) study employed cis-expression quantitative trait loci (cis-eQTLs) to assess the causal relationships between gene expression and AF. After achieving significance in the UK Biobank following multiple testing adjustments and validation in FinnGen, colocalization analysis and protein quantitative trait loci (pQTL) analysis were carried out.

Results

In the UK Biobank, genetic expression of 65 genes showed significant correlation with AF risk, and 15 were replicated in FinnGen. Colocalization analysis identified three primary candidates: WDR1, ESR2, and CXCL10, with significant associations in inverse variance-weighted (IVW) analysis. ESR2 showed a positive association with AF (OR = 1.403; 95 % CI: 1.200–1.640), while WDR1 (OR = 0.800; 95 % CI: 0.734–0.871) and CXCL10 (OR = 0.814; 95 % CI: 0.738–0.897) were negatively associated. Given the absence of pQTL data for ESR2 and WDR1, pQTL analysis focused exclusively on CXCL10 (OR = 0.59; 95 % CI: 0.43–0.82). Results from both the MR-Egger and weighted median methods were predominantly in agreement with that from IVW analyses.