Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers.
Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers.
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DOI：
10.1074/mcp.m800453-mcp200
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发表时间：
2009-06
期刊：
影响因子：
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通讯作者：
Clinical Genomic and Proteomic AMD Study Group
中科院分区：
文献类型：
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作者：
Gu J;Pauer GJ;Yue X;Narendra U;Sturgill GM;Bena J;Gu X;Peachey NS;Salomon RG;Hagstrom SA;Crabb JW;Clinical Genomic and Proteomic AMD Study Group
年龄相关性黄斑变性（AMD）是一种进行性疾病，是严重视力丧失的主要原因。为了发现早期识别AMD易感性的工具，我们评估了蛋白质组学和基因组学AMD生物标志物的联合预测能力。我们用ELISA法定量测定了916例AMD和488例对照供者血浆中羧基乙基吡咯（CEP）氧化蛋白修饰和CEP自身抗体。CEP加合物是由视网膜中丰富的含有二十二碳六烯酸的脂质氧化而产生的。AMD血浆中平均CEP加合物和自身抗体水平分别升高了约60%和约30%。两种CEP标志物升高的优势比在AMD患者中比在对照患者中高出3倍或更多。对与年龄相关性黄斑病变易感性2 （ARMS2）、高温需要因子A1 （HTRA1）、补体因子H和补体C3相关的AMD风险多态性进行基因分型，并根据基因分型单独或联合CEP标记预测AMD的风险。CEP标记物和风险基因型升高的患者患AMD的风险比仅基于基因型的患者高2 - 3倍。携带ARMS2和HTRA1风险等位基因的AMD供体最有可能出现CEP标记升高。结果令人信服地表明，在广泛的年龄范围内，AMD血浆中平均CEP标志物水平较高。接受者工作特征曲线表明，CEP标记单独区分AMD和对照血浆供者的准确率为76%，与基因组标记结合可提供高达80%的区分准确率。血浆CEP标记物水平受到几个值得进一步研究的人口统计学和健康因素的轻微改变。我们的结论是，CEP血浆生物标志物，特别是与基因组标志物的结合，为评估这种致盲的多因素疾病的易感性提供了一个潜在的预警系统。
Age-related macular degeneration (AMD) is a progressive disease and major cause of severe visual loss. Toward the discovery of tools for early identification of AMD susceptibility, we evaluated the combined predictive capability of proteomic and genomic AMD biomarkers. We quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. CEP adducts are uniquely generated from oxidation of docosahexaenoate-containing lipids that are abundant in the retina. Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by ∼60 and ∼30%, respectively. The odds ratio for both CEP markers elevated was 3-fold greater or more in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high temperature requirement factor A1 (HTRA1), complement factor H, and complement C3, and the risk of AMD was predicted based on genotype alone or in combination with the CEP markers. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2–3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with ∼76% accuracy and in combination with genomic markers provide up to ∼80% discrimination accuracy. Plasma CEP marker levels were altered slightly by several demographic and health factors that warrant further study. We conclude that CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for assessing susceptibility to this blinding, multifactorial disease.