{"title":"降脂药物靶点对糖尿病视网膜病变遗传关联的影响。","authors":"Xue Zhang, Kuanlu Fan, Jiaxin Li","doi":"10.5114/aoms/199622","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Lipid metabolism is pivotal in diabetic retinopathy (DR) development. Nevertheless, the relationship between lipid-lowering drugs and the risk of DR remains a topic of debate. This study employed Mendelian randomization (MR) to investigate the potential effects of pharmacological lipid-lowering targets on DR and to clarify the causal association between blood lipid characteristics and DR.</p><p><strong>Material and methods: </strong>The data comprised genetic variations related to lipid traits and genetic variations associated with lipid-lowering drug targets obtained from the Global Lipid Consortium. Total DR, non-proliferative DR (NPDR), and proliferative DR (PDR) were sourced from the Finnish R9 database. Lipid-lowering drug targets were tested using inverse variance-weighted MR (IVW-MR) and statistics-based MR (SMR). Colocalization and mediation analysis were conducted to validate the results and explore potential mediating factors.</p><p><strong>Results: </strong>A reduced risk of total DR and NPDR was associated with genetically improved 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (OR = 0.62; 95% CI: 0.46-0.83; <i>p</i> = 1.30 × 10<sup>-2</sup>; OR = 0.49; 95% CI: 0.34-0.70; <i>p</i> = 9.70 × 10<sup>-4</sup>). Strong colocalization (PP.H4 = 0.85) was observed between whole blood tissue HMGCR expression and a significant MR relationship with total DR (OR = 0.66; 95% CI: 0.52-0.85; <i>p</i> = 7.31 × 10<sup>-4</sup>). Furthermore, body mass index (BMI) and glycated hemoglobin (HbA<sub>1c</sub>) are critical factors that mediate the impact of HMGCR and apolipoprotein B (APOB) on DR risk.</p><p><strong>Conclusions: </strong>This Mendelian randomization study suggests that abnormalities in triglyceride (TG) levels serve as a pathogenic element in DR. Of the nine lipid-lowering drug targets assessed, HMGCR and APOB have emerged as potential promising targets for managing NPDR. These findings underscore the importance of controlling both BMI and HbA<sub>1c</sub> levels to optimize outcomes in diabetic patients at risk for DR. The therapeutic mechanisms of HMGCR and APOB in DR go beyond lipid lowering alone, and a multimodal lipid-lowering strategy should be selected early and comprehensively to address the patient's medical conditions.</p>","PeriodicalId":8278,"journal":{"name":"Archives of Medical Science","volume":"21 4","pages":"1152-1163"},"PeriodicalIF":3.3000,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509816/pdf/","citationCount":"0","resultStr":"{\"title\":\"Impact of lipid-lowering drug targets on genetic associations with diabetic retinopathy.\",\"authors\":\"Xue Zhang, Kuanlu Fan, Jiaxin Li\",\"doi\":\"10.5114/aoms/199622\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Lipid metabolism is pivotal in diabetic retinopathy (DR) development. Nevertheless, the relationship between lipid-lowering drugs and the risk of DR remains a topic of debate. This study employed Mendelian randomization (MR) to investigate the potential effects of pharmacological lipid-lowering targets on DR and to clarify the causal association between blood lipid characteristics and DR.</p><p><strong>Material and methods: </strong>The data comprised genetic variations related to lipid traits and genetic variations associated with lipid-lowering drug targets obtained from the Global Lipid Consortium. Total DR, non-proliferative DR (NPDR), and proliferative DR (PDR) were sourced from the Finnish R9 database. Lipid-lowering drug targets were tested using inverse variance-weighted MR (IVW-MR) and statistics-based MR (SMR). Colocalization and mediation analysis were conducted to validate the results and explore potential mediating factors.</p><p><strong>Results: </strong>A reduced risk of total DR and NPDR was associated with genetically improved 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (OR = 0.62; 95% CI: 0.46-0.83; <i>p</i> = 1.30 × 10<sup>-2</sup>; OR = 0.49; 95% CI: 0.34-0.70; <i>p</i> = 9.70 × 10<sup>-4</sup>). Strong colocalization (PP.H4 = 0.85) was observed between whole blood tissue HMGCR expression and a significant MR relationship with total DR (OR = 0.66; 95% CI: 0.52-0.85; <i>p</i> = 7.31 × 10<sup>-4</sup>). Furthermore, body mass index (BMI) and glycated hemoglobin (HbA<sub>1c</sub>) are critical factors that mediate the impact of HMGCR and apolipoprotein B (APOB) on DR risk.</p><p><strong>Conclusions: </strong>This Mendelian randomization study suggests that abnormalities in triglyceride (TG) levels serve as a pathogenic element in DR. Of the nine lipid-lowering drug targets assessed, HMGCR and APOB have emerged as potential promising targets for managing NPDR. These findings underscore the importance of controlling both BMI and HbA<sub>1c</sub> levels to optimize outcomes in diabetic patients at risk for DR. 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引用次数: 0
摘要
脂质代谢是糖尿病视网膜病变（DR）发展的关键。然而，降脂药物与DR风险之间的关系仍然是一个有争议的话题。本研究采用孟德尔随机化（Mendelian randomization， MR）研究降脂药物靶点对DR的潜在影响，并阐明血脂特征与DR之间的因果关系。材料和方法：数据包括与脂质性状相关的遗传变异和与降脂药物靶点相关的遗传变异，这些遗传变异均来自全球脂质联盟。总DR、非增殖性DR （NPDR）和增殖性DR （PDR）来源于芬兰R9数据库。采用逆方差加权磁共振（IVW-MR）和基于统计的磁共振（SMR）检测降脂药物靶点。通过共地化和中介分析来验证结果并探索潜在的中介因素。结果：总DR和NPDR的风险降低与基因改良的3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）相关（OR = 0.62; 95% CI: 0.46-0.83; p = 1.30 × 10-2; OR = 0.49; 95% CI: 0.34-0.70; p = 9.70 × 10-4）。全血HMGCR表达与MR与总DR之间存在强共定位（PP.H4 = 0.85） （OR = 0.66; 95% CI: 0.52-0.85; p = 7.31 × 10-4）。此外，体重指数（BMI）和糖化血红蛋白（HbA1c）是介导HMGCR和载脂蛋白B （APOB）对DR风险影响的关键因素。结论：这项孟德尔随机化研究表明，甘油三酯（TG）水平异常是dr的致病因素。在评估的9个降脂药物靶点中，HMGCR和APOB已成为治疗NPDR的潜在有希望的靶点。这些发现强调了控制BMI和HbA1c水平对于优化DR风险的糖尿病患者预后的重要性。HMGCR和APOB在DR中的治疗机制不仅仅是单纯的降脂，应及早综合选择多模式降脂策略，以解决患者的医疗状况。
Impact of lipid-lowering drug targets on genetic associations with diabetic retinopathy.
Introduction: Lipid metabolism is pivotal in diabetic retinopathy (DR) development. Nevertheless, the relationship between lipid-lowering drugs and the risk of DR remains a topic of debate. This study employed Mendelian randomization (MR) to investigate the potential effects of pharmacological lipid-lowering targets on DR and to clarify the causal association between blood lipid characteristics and DR.
Material and methods: The data comprised genetic variations related to lipid traits and genetic variations associated with lipid-lowering drug targets obtained from the Global Lipid Consortium. Total DR, non-proliferative DR (NPDR), and proliferative DR (PDR) were sourced from the Finnish R9 database. Lipid-lowering drug targets were tested using inverse variance-weighted MR (IVW-MR) and statistics-based MR (SMR). Colocalization and mediation analysis were conducted to validate the results and explore potential mediating factors.
Results: A reduced risk of total DR and NPDR was associated with genetically improved 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (OR = 0.62; 95% CI: 0.46-0.83; p = 1.30 × 10-2; OR = 0.49; 95% CI: 0.34-0.70; p = 9.70 × 10-4). Strong colocalization (PP.H4 = 0.85) was observed between whole blood tissue HMGCR expression and a significant MR relationship with total DR (OR = 0.66; 95% CI: 0.52-0.85; p = 7.31 × 10-4). Furthermore, body mass index (BMI) and glycated hemoglobin (HbA1c) are critical factors that mediate the impact of HMGCR and apolipoprotein B (APOB) on DR risk.
Conclusions: This Mendelian randomization study suggests that abnormalities in triglyceride (TG) levels serve as a pathogenic element in DR. Of the nine lipid-lowering drug targets assessed, HMGCR and APOB have emerged as potential promising targets for managing NPDR. These findings underscore the importance of controlling both BMI and HbA1c levels to optimize outcomes in diabetic patients at risk for DR. The therapeutic mechanisms of HMGCR and APOB in DR go beyond lipid lowering alone, and a multimodal lipid-lowering strategy should be selected early and comprehensively to address the patient's medical conditions.
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