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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid
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Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid

机译：具有年龄相关性黄斑变性风险的补体因子H变异纯合子个体的脉络膜CRP水平升高

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摘要

Polymorphisms in the complement factor H gene (CFH) are associated with a significantly increased risk for, or protection against, the development of age-related macular degeneration (AMD). The most documented risk-conferring single-nucleoticle polymorphism results in a tyrosine-to-histidine substitution at position 402 (Y402H) of the CFH protein. In this work, we examined the ocular distributions and relative abundance of CFH, several CFH-binding proteins, and abundant serum proteins in the retinal pigmented epithelium (RPE), Bruch's membrane, and choroid (RPE-choroid) in CFH homozygotes possessing either the "at-risk" 402HH or "normal" 402YY variants. Although CFH immunoreactivity is high in the choroid and in drusen, no differences in CFH-labeling patterns between genotypes are apparent. In contrast, at-risk individuals have significantly higher levels of the CFH-binding protein, C-reactive protein (CRP), in the choroidal stroma. Immunoblots confirm that at-risk individuals have approximate to 2.5-fold higher levels of CRP in the RPE-choroid; no significant differences in the levels of CFH or other serum proteins are detected. Similarly, we find no differences in CFH transcription levels in the RPE-choroid nor evidence for local ocular CRP transcription. Increased levels of CRP in the choroid may reflect a state of chronic inflammation that is a by-product of attenuated CFH complement-inhibitory activity in those who possess the CFH at-risk allele. Because the CRP-binding site in CFH lies within the domain containing the Y402H polymorphism, it is also possible that the AMD risk-conferring allele alters the binding properties of CFH, thereby leading to choroidal CRP deposition, contributing to AMD pathogenesis.
机译：补体因子H基因（CFH）的多态性与年龄相关性黄斑变性（AMD）的发展或预防风险显着相关。最有据可证的赋予风险的单核苷酸多态性会导致CFH蛋白在位置402（Y402H）处被酪氨酸取代为组氨酸。在这项工作中，我们检查了CFH纯合子中视网膜色素上皮（RPE），Bruch膜和脉络膜（RPE-脉络膜）的CFH的眼分布和相对丰度，几种CFH结合蛋白和丰富的血清蛋白。 “高风险” 402HH或“正常” 402YY变体。尽管CFH在脉络膜和玻璃疣中的免疫反应性很高，但是在基因型之间CFH标记方式上没有差异是显而易见的。相反，处于危险中的个体在脉络膜基质中的CFH结合蛋白，C反应蛋白（CRP）的水平明显更高。免疫印迹证实，处于危险中的个体在RPE脉络膜中的CRP水平大约高出2.5倍。没有检测到CFH或其他血清蛋白水平的显着差异。同样，我们没有发现RPE脉络膜中CFH转录水平的差异，也没有发现局部眼部CRP转录的证据。脉络膜中CRP的水平升高可能反映出慢性炎症状态，这是患有CFH高危等位基因的人CFH补体抑制活性减弱的副产物。由于CFH中的CRP结合位点位于包含Y402H多态性的结构域内，因此，具有AMD风险的等位基因可能会改变CFH的结合特性，从而导致脉络膜CRP沉积，从而导致AMD发病。

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