老年黃斑變性是全世界范圍內失明的主要原因之一,，尤其是在發(fā)達國家中，在那里絕大部分病人沒有已知治療或治愈的方法,。一項新研究確定了表達水平可鑒定AMD患者及其亞型的基因,。
據估計,，6.5%的40歲以上的美國人都患AMD。有一種可遺傳的遺傳危險因素,，對于吸煙者和暴露于紫外線光的人風險也增加,。全基因組研究表明，涉及先天免疫系統和脂肪代謝的基因也與這種疾病有關,。然而,，這些先前的研究沒有檢查出AMD與正常眼睛之間的基因表達差異。
為了闡明這個問題,，加州大學圣塔芭芭拉分校,、猶他大學約翰莫蘭眼科中心和愛荷華大學的研究人員結合彼此力量，用一個人類捐贈眼庫來確定AMD中上調的基因,。這些基因識別AMD的能力在一組獨立樣本中測試,。
研究小組發(fā)現了50多個基因，這些基因在AMD中表達水平高于正常,，前20個能預測臨床AMD診斷,。RPE-脈絡膜（位于視網膜下的組織）中過量表達基因包括炎癥反應元件，而在視網膜中研究人員發(fā)現涉及傷口愈合與補體級聯的基因,，其中補體級聯是天然免疫系統的一部分,。他們發(fā)現視網膜基因表達水平與AMD后期的嚴重程度相匹配。
這些基因不僅能鑒定具臨床特征的AMD患者,，也能區(qū)分不同晚期類型,，這些基因中的某些出現與AMD的臨床前期相關。這表明,，它們可能參與驅動疾病的關鍵過程?，F在，我們知道許多參與此疾病的基因的身份與功能,，我們能開始觀察它們來開發(fā)新診斷方法,，尋找所有形式AMD治療方法的新靶標。（生物谷bioon.com）
doi:10.1186/PREACCEPT-1418491035586234
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Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks
Aaron M Newman, Natasha B Gallo, Lisa S Hancox, Norma J Miller, Carolyn M Radeke, Michelle A Maloney, James B Cooper, Gregory S Hageman, Don H Anderson, Lincoln V Johnson, Monte J Radeke
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.
