Guo Yujin, Zhao Jing, Chen Zhiqing
Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
Comb Chem High Throughput Screen. 2025 May 5. doi: 10.2174/0113862073373085250418113858.
Inflammation is a key mechanism underlying age-related macular degeneration (AMD); however, the specific circulating inflammatory proteins involved remain unclear. This study investigated the causal relationship between 91 circulating inflammatory proteins and AMD using a two-sample Mendelian randomization (MR) approach.
We conducted a two-sample magnetic resonance imaging MR analysis using genomewide association study (GWAS) data. Five MR methodologies were applied, with inverse variance weighting (IVW) as the primary approach. We applied false discovery rate (FDR) correction to mitigate false positives. Sensitivity analyses were performed to assess horizontal pleiotropy and heterogeneity. Additionally, Steiger's test, reverse MR analysis, and linkage disequilibrium score regression (LDSC) were used to validate the results.
Five inflammatory proteins demonstrated significant associations with overall AMD, including three associated with wet AMD and one associated with dry AMD. LDSC analysis indicated that, except for fibroblast growth factor-19, no genetic correlation confounded the causal relationships. Additionally, the expression of the identified proteins was unaffected by the genetic prediction of AMD.
This study highlights the causal relationship between specific inflammatory proteins and AMD, emphasizing their potential roles in AMD pathogenesis and potential therapeutic targets.
炎症是年龄相关性黄斑变性（AMD）的关键潜在机制；然而，具体涉及的循环炎症蛋白仍不清楚。本研究采用两样本孟德尔随机化（MR）方法，调查了91种循环炎症蛋白与AMD之间的因果关系。
我们使用全基因组关联研究（GWAS）数据进行了两样本磁共振成像MR分析。应用了五种MR方法，以逆方差加权（IVW）作为主要方法。我们应用错误发现率（FDR）校正来减轻假阳性。进行敏感性分析以评估水平多效性和异质性。此外，使用Steiger检验、反向MR分析和连锁不平衡评分回归（LDSC）来验证结果。
五种炎症蛋白与总体AMD表现出显著关联，其中三种与湿性AMD相关，一种与干性AMD相关。LDSC分析表明，除成纤维细胞生长因子-19外，没有遗传相关性混淆因果关系。此外，所鉴定蛋白的表达不受AMD遗传预测的影响。
本研究突出了特定炎症蛋白与AMD之间的因果关系，强调了它们在AMD发病机制中的潜在作用以及潜在治疗靶点。
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