Integrating Metabolomics, Genomics, and Disease Pathways in Age-Related Macular Degeneration The EYE-RISK Consortium
Integrating Metabolomics, Genomics, and Disease Pathways in Age-Related Macular Degeneration The EYE-RISK Consortium
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DOI：
10.1016/j.ophtha.2020.06.020
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发表时间：
2020-12-01
期刊：
影响因子：
13.7
通讯作者：
den Hollander, Anneke, I
中科院分区：
文献类型：
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作者：
Acar, Ilhan E.;Lores-Motta, Laura;den Hollander, Anneke, I
目的：本研究旨在通过进行迄今为止最大的 AMD 代谢组关联分析来鉴定与年龄相关性黄斑变性 (AMD) 相关的代谢物，并确定 AMD 相关遗传变异对代谢物水平的影响，并研究已识别的代谢物与补体系统活性（AMD 相关疾病的主要途径之一）之间的关联。设计：病例对照关联 参与者：由 2267 名 AMD 患者和 4266 名对照参与者组成的 5 个欧洲队列。方法：使用高通量质子核磁共振代谢组学平台进行代谢组学，该平台可以量化 146 种代谢物测量值和 79 种衍生值。使用单变量逻辑回归分析研究代谢组 AMD 关联。使用线性回归研究了 52 种 AMD 相关遗传变异对已识别代谢物的影响。此外，使用线性回归研究了已鉴定的代谢物与补体途径活性（由 C3d 与 C3 比率定义）之间的关联。主要结果指标：与 AMD 相关的代谢物。结果：我们鉴定了 60 种与 AMD 显着相关的代谢物，包括大和超大高密度脂蛋白 (HDL) 亚类水平升高以及非常大的高密度脂蛋白 (HDL) 亚类水平降低。 低密度脂蛋白（VLDL）、氨基酸和柠檬酸盐。在 52 个 AMD 相关基因变异中，7 个变异与 34 种已识别的代谢物显着相关。位于参与脂质代谢的基因（ABCA1、CETP、APOE 和 LIPC）中或附近的遗传变异与属于大和超大 HDL 亚类的代谢物的关联性最强。此外，60 种代谢物中有 57 种与补体激活水平显着相关，与 AMD 状态无关。大HDL和超大HDL水平增加以及VLDL和氨基酸水平降低与补体激活增加相关。结论：脂蛋白水平与AMD相关的遗传变异相关，而必需氨基酸的减少可能表明AMD的营养缺乏。我们观察到绝大多数 AMD 相关代谢物与全身补体激活水平之间存在很强的关联，而与 AMD 状态无关。这可能表明AMD主要疾病途径之间存在生物相互作用，并表明可能需要同时针对多种途径才能成功治疗AMD。 (C) 2020 年，美国眼科学会。这是一篇基于 CC BY-NC-ND 许可的开放获取文章
Purpose: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways.Design: Case-control association analysis of metabolomics data.Participants: Five European cohorts consisting of 2267 AMD patients and 4266 control participants.Methods: Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. MetabolomeeAMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression.Main Outcome Measures: Metabolites associated with AMD.Results: We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high- density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation.Conclusions: Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD. (C) 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license