Chen Chengming, Xie Tingke, Zhang Huan, Chang Lifu, Lan Yanyan, Fan Chao, Wei Dongyu, Wang Xiaolan, Liu Sida, Chen Yixuan, Chen Yuhao, Wang Xuejiao, Yan Xiaolong, Shang Lei, Tao Liyuan, Han Jing
Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Ophthalmology, The 900th Hospital of Joint Logistic Support Force, PLA (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China.
Invest Ophthalmol Vis Sci. 2025 Sep 2;66(12):24. doi: 10.1167/iovs.66.12.24.
To explore the causal links between antihypertension drugs usage and age-related macular degeneration (AMD).
Multiple genetic analyses, including summary data-based Mendelian randomization (SMR), traditional MR, and colocalization analysis, were used to explore the causal associations between antihypertension drugs and AMD. Clinical data from the UK Biobank and the National Health and Nutrition Examination Survey (NHANES) was applied to refined risk assessment of specific antihypertensive medications in the context of AMD development. In vitro and in vivo oxidative stress models, mediated by NaIO3, were utilized to study the impact of specific antihypertensive drugs and target genes on AMD pathogenesis.
Genetic analyses substantiated the causal relationship between increased SLC12A3 expression and a lowered AMD risk. Colocalization analysis supported the shared causal attributes between SLC12A3 expression and AMD. Cross-sectional analysis results based on UK Biobank indicated that AMD risk was significantly lower in participants taking thiazide diuretics with other antihypertensives or not on antihypertensives compared to those on thiazides alone. The results based on NHANES support the above results. In vivo and in vitro experiments showed that thiazide diuretics worsened retinal damage in AMD mouse models, and SLC12A3 knockdown disrupted the balance of oxidative stress in retinal pigment epithelium (RPE) cells. Further molecular mechanism experiments showed that SLC12A3 knockdown promoted retinal degeneration by regulating RPE ferroptosis through activation of the Nrf2/HO-1 pathway.
Our study underscores a notable causal association between thiazide diuretic use and AMD risk and reveals a potential mechanism by which inhibition or downregulation of SLC12A3 (sodium-chloride cotransporter [NCC]) contributes to AMD progression. However, deeper exploration is needed to enhance the accuracy and validity of our findings.
探讨抗高血压药物使用与年龄相关性黄斑变性（AMD）之间的因果关系。
采用多种遗传分析方法，包括基于汇总数据的孟德尔随机化（SMR）、传统MR和共定位分析，以探讨抗高血压药物与AMD之间的因果关联。来自英国生物银行和美国国家健康与营养检查调查（NHANES）的临床数据被用于在AMD发生背景下对特定抗高血压药物进行精细风险评估。利用由碘酸钠介导的体外和体内氧化应激模型，研究特定抗高血压药物和靶基因对AMD发病机制的影响。
遗传分析证实了SLC12A3表达增加与降低的AMD风险之间的因果关系。共定位分析支持SLC12A3表达与AMD之间存在共同的因果属性。基于英国生物银行的横断面分析结果表明，与单独使用噻嗪类利尿剂的参与者相比，同时服用噻嗪类利尿剂与其他抗高血压药物或未服用抗高血压药物的参与者患AMD的风险显著降低。基于NHANES的结果支持上述结果。体内和体外实验表明，噻嗪类利尿剂会加重AMD小鼠模型中的视网膜损伤，而敲低SLC12A3会破坏视网膜色素上皮（RPE）细胞中的氧化应激平衡。进一步的分子机制实验表明，敲低SLC12A3通过激活Nrf2/HO-1途径调节RPE铁死亡，从而促进视网膜变性。
我们的研究强调了噻嗪类利尿剂使用与AMD风险之间存在显著的因果关联，并揭示了抑制或下调SLC12A3（氯化钠共转运体[NCC]）导致AMD进展的潜在机制。然而，需要更深入的探索以提高我们研究结果的准确性和有效性。
