Johnson P T, Betts K E, Radeke M J, Hageman G S, Anderson D H, Johnson L V
Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-5060, USA.
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17456-61. doi: 10.1073/pnas.0606234103. Epub 2006 Nov 1.
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-nucleotide 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 approximately 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.
补体因子H基因（CFH）的多态性与年龄相关性黄斑变性（AMD）发生风险的显著增加或预防相关。记录最多的风险赋予单核苷酸多态性导致CFH蛋白第402位（Y402H）的酪氨酸被组氨酸取代。在这项研究中，我们检测了具有“风险”402HH或“正常”402YY变体的CFH纯合子的视网膜色素上皮（RPE）、布鲁赫膜和脉络膜（RPE-脉络膜）中CFH、几种CFH结合蛋白和丰富血清蛋白的眼部分布及相对丰度。尽管CFH免疫反应性在脉络膜和玻璃膜疣中较高，但基因型之间CFH标记模式没有明显差异。相比之下，有风险个体脉络膜基质中CFH结合蛋白C反应蛋白（CRP）水平显著更高。免疫印迹证实，有风险个体的RPE-脉络膜中CRP水平约高2.5倍；未检测到CFH或其他血清蛋白水平有显著差异。同样，我们发现RPE-脉络膜中CFH转录水平没有差异，也没有局部眼部CRP转录的证据。脉络膜中CRP水平升高可能反映了一种慢性炎症状态，这是那些携带CFH风险等位基因的个体中CFH补体抑制活性减弱的副产品。由于CFH中的CRP结合位点位于包含Y402H多态性的结构域内，也有可能赋予AMD风险的等位基因改变了CFH的结合特性，从而导致脉络膜CRP沉积，促进AMD发病机制。
