老年黃斑變性是全世界范圍內(nèi)失明的主要原因之一,，尤其是在發(fā)達(dá)國(guó)家中,，在那里絕大部分病人沒(méi)有已知治療或治愈的方法,。一項(xiàng)新研究確定了表達(dá)水平可鑒定AMD患者及其亞型的基因,。
據(jù)估計(jì)，6.5%的40歲以上的美國(guó)人都患AMD,。有一種可遺傳的遺傳危險(xiǎn)因素,，對(duì)于吸煙者和暴露于紫外線光的人風(fēng)險(xiǎn)也增加。全基因組研究表明,，涉及先天免疫系統(tǒng)和脂肪代謝的基因也與這種疾病有關(guān),。然而，這些先前的研究沒(méi)有檢查出AMD與正常眼睛之間的基因表達(dá)差異,。
為了闡明這個(gè)問(wèn)題,，加州大學(xué)圣塔芭芭拉分校、猶他大學(xué)約翰莫蘭眼科中心和愛荷華大學(xué)的研究人員結(jié)合彼此力量,，用一個(gè)人類捐贈(zèng)眼庫(kù)來(lái)確定AMD中上調(diào)的基因,。這些基因識(shí)別AMD的能力在一組獨(dú)立樣本中測(cè)試。
研究小組發(fā)現(xiàn)了50多個(gè)基因,，這些基因在AMD中表達(dá)水平高于正常,，前20個(gè)能預(yù)測(cè)臨床AMD診斷。RPE-脈絡(luò)膜（位于視網(wǎng)膜下的組織）中過(guò)量表達(dá)基因包括炎癥反應(yīng)元件,，而在視網(wǎng)膜中研究人員發(fā)現(xiàn)涉及傷口愈合與補(bǔ)體級(jí)聯(lián)的基因,，其中補(bǔ)體級(jí)聯(lián)是天然免疫系統(tǒng)的一部分。他們發(fā)現(xiàn)視網(wǎng)膜基因表達(dá)水平與AMD后期的嚴(yán)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(xiàn)與AMD的臨床前期相關(guān),。這表明,，它們可能參與驅(qū)動(dòng)疾病的關(guān)鍵過(guò)程。現(xiàn)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(lái)開發(fā)新診斷方法,，尋找所有形式AMD治療方法的新靶標(biāo),。（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.
