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年龄相关性黄斑变性遗传学的临床应用

Clinical applications of age-related macular degeneration genetics.

作者信息

SanGiovanni John Paul, Chew Emily Y

机构信息

National Eye Institute, Clinical Trials Branch, Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892.

出版信息

Cold Spring Harb Perspect Med. 2014 Aug 14;4(10):a017228. doi: 10.1101/cshperspect.a017228.

Abstract

Understanding genetic causes of age-related macular degeneration (AMD) will eventually yield effective discoveries and improvements in predictive/prognostic methods. These include, but are not limited to, reliable disease prediction (screening for increased discrimination of clinical risk), differential classification of AMD subtypes with biomarkers (development of risk-linked molecular taxonomies), selection of optimal preventive and therapeutic interventions (guided by a biologically meaningful understanding of treatment response), and drug dosing. In this review, we discuss clinical applications informed by key findings in AMD genetics, and provide commentary on leveraging extant and forthcoming evidence to improve AMD risk prediction, AMD classification, and knowledge on the genetic basis of drug activity and toxicity. Advances in translating AMD genetics findings for AMD risk prediction require development of a genetics-based causality for AMD incidence and progression. Molecular subtyping of AMD phenotypes requires a set of dynamic biomarkers presenting prognostic value; although these have yet to be identified, the formation of multidisciplinary teams and their participation in large-scale consortia may yield promising results. Drugs targeting complement and vascular endothelial growth factor (VEGF) systems are under evaluation, and forthcoming work on rare variants and noncoding DNA in AMD pathogenesis will likely reveal biochemical pathways enriched with AMD-associated genetic variants. Pharmacologic targets in these pathways may inform a rational and effective therapeutic approach to preventing and treating this sight-threatening disease.

摘要

了解年龄相关性黄斑变性(AMD)的遗传病因最终将在预测/预后方法方面带来有效的发现和改进。这些包括但不限于可靠的疾病预测(提高临床风险辨别力的筛查)、利用生物标志物对AMD亚型进行差异分类(开发与风险相关的分子分类法)、选择最佳的预防和治疗干预措施(基于对治疗反应的生物学意义上的理解)以及药物剂量确定。在本综述中,我们讨论了由AMD遗传学的关键发现所推动的临床应用,并就利用现有和即将出现的证据来改善AMD风险预测、AMD分类以及关于药物活性和毒性的遗传基础的知识发表评论。将AMD遗传学发现转化为AMD风险预测的进展需要建立基于遗传学的AMD发病和进展的因果关系。AMD表型的分子亚型分类需要一组具有预后价值的动态生物标志物;尽管尚未确定这些标志物,但多学科团队的组建及其参与大规模联盟可能会产生有前景的结果。针对补体和血管内皮生长因子(VEGF)系统的药物正在评估中,并且即将开展的关于AMD发病机制中罕见变异和非编码DNA的研究可能会揭示富含AMD相关遗传变异的生化途径。这些途径中的药理学靶点可能为预防和治疗这种威胁视力的疾病提供合理有效的治疗方法。

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