文献标题：Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks

　　文献来源：Genome Med. 2012 Feb 204;4:16. [Epub ahead of print]

　　期刊影响因子：2.092

　　PMID：暂无

　　老年黄斑变性是全世界范围内失明的主要原因之一，尤其是在发达国家中，在那里绝大部分病人没有已知治疗或治愈的方法。一项新研究确定了表达水平可鉴定AMD患者及其亚型的基因。

　　据估计，6.5%的40岁以上的美国人都患AMD。有一种可遗传的遗传危险因素，对于吸烟者和暴露于紫外线光的人风险也增加。全基因组研究表明，涉及先天免疫系统和脂肪代谢的基因也与这种疾病有关。然而，这些先前的研究没有检查出AMD与正常眼睛之间的基因表达差异。

　　AMD患者中心视力损害，视物变形

　　为了阐明这个问题，加州大学圣塔芭芭拉分校、犹他大学约翰莫兰眼科中心和爱荷华大学的研究人员结合彼此力量，用一个人类捐赠眼库来确定AMD中上调的基因。这些基因识别AMD的能力在一组独立样本中测试。

　　研究小组发现了50多个基因，这些基因在AMD中表达水平高于正常，前20个能预测临床AMD诊断。RPE-脉络膜(位于视网膜下的组织)中过量表达基因包括炎症反应元件，而在视网膜中研究人员发现涉及伤口愈合与补体级联的基因，其中补体级联是天然免疫系统的一部分。他们发现视网膜基因表达水平与AMD后期的严重程度相匹配。

　　这些基因不仅能鉴定具临床特征的AMD患者，也能区分不同晚期类型，这些基因中的某些出现与AMD的临床前期相关。这表明，它们可能参与驱动疾病的关键过程。现在，我们知道许多参与此疾病的基因的身份与功能，我们能开始观察它们来开发新诊断方法，寻找所有形式AMD治疗方法的新靶标。

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　　Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks

　　Abstact

　　Background：Age-related macular degeneration (AMD) is a leading cause of blindness that affects the central region of the retinal pigmented epithelium (RPE), choroid, and neural retina. Initially characterized by an accumulation of sub-RPE deposits, AMD leads to progressive retinal degeneration, and in advanced cases, irreversible vision loss. Although genetic analysis, animal models, and cell culture systems have yielded important insights into AMD, the molecular pathways underlying AMD's onset and progression remain poorly delineated. We sought to better understand the molecular underpinnings of this devastating disease by performing the first comparative transcriptome analysis of AMD and normal human donor eyes.

　　Methods：RPE-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 AMD and 11 potential pre-AMD human donor eyes. Transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally-enriched protein association networks. Selected genes of high significance were validated using an independent donor cohort.

　　Results：We identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in RPE-choroid AMD phenotypes. Using a machine learning model and a second donor cohort, we show that the top twenty global genes are predictive of AMD clinical diagnosis. We also discovered functionally-enriched gene sets in the RPE-choroid that delineate the advanced AMD phenotypes, neovascular AMD and geographic atrophy. Moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased AMD severity. Based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be involved in AMD pathogenesis.

　　Conclusions：We discovered new global biomarkers and gene expression signatures of AMD. These results are consistent with a model whereby cell-based inflammatory responses represent a central feature of AMD etiology, and depending on genetics, environment, or stochastic factors, may give rise to the advanced AMD phenotypes characterized by angiogenesis and/or cell death. Genes regulating these immunological activities, along with numerous other genes identified here, represent promising new targets for AMD-directed therapeutics and diagnostics.