Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Ophthalmology. 2012 Feb;119(2):339-46. doi: 10.1016/j.ophtha.2011.07.056. Epub 2011 Nov 30.
PURPOSE: Systemic complement activation is associated with age-related macular degeneration (AMD) and has mainly been attributed to a risk allele in the complement factor H (CFH) gene. Whether other important AMD genes also influence complement activation is unclear. In the present case-control study, complement activity and concentrations of complement components and their activation products are measured in AMD patients and in unaffected controls and correlated with genetic variants in the CFH, ARMS2, C3, CFI, and CFB genes. DESIGN: Case-control study. PARTICIPANTS: A cohort of 197 confirmed AMD patients and 150 unaffected age-matched controls were recruited prospectively for the study. METHODS: Hemolytic complement assays (AP50, CP50, and LP50), complement components (C3, CFB, CFI, and CFH), and the activation products (C3d, C5a, and SC5b-9) were analyzed in serum or plasma. The DNA samples were genotyped for 5 single nucleotide polymorphisms (SNPs) previously associated with AMD in the CFH, ARMS2, C3, CFB, and CFI genes. MAIN OUTCOME MEASURES: Complement concentrations and their associations with SNPs in the CFH, ARMS2, C3, CFB, and CFI genes. RESULTS: The AMD patients had increased activation of the alternative complement pathway (P = 0.003) and elevated levels of complement activation components C3d (P<0.0001) and C5a (P<0.0001), CFB (P<0.0001), and an increased C3d/C3 ratio (P<0.0001) calculated as a measure of C3 activation. While the CFH risk genotype was significantly associated with the elevated C3d/C3 ratios obtained, in the absence of CFH risk alleles the ARMS2 risk genotype also showed significantly increased levels of complement activation (P = 0.013). Furthermore, the carriers of the CFB protective allele had lower CFB concentrations. CONCLUSIONS: The current study found evidence showing that in AMD risk alleles in CFH and ARMS2 are independently associated with complement activation. Especially the C3d/C3 ratio seems to be a strong marker for AMD. The findings suggest that CFH and ARMS2 share a common pathway in the pathogenesis of AMD.
目的：全身性补体激活与年龄相关性黄斑变性（AMD）有关，主要归因于补体因子 H（CFH）基因中的风险等位基因。其他重要的 AMD 基因是否也会影响补体激活尚不清楚。在本病例对照研究中，测量了 AMD 患者和无影响对照者的补体活性以及补体成分及其激活产物的浓度，并与 CFH、ARMS2、C3、CFI 和 CFB 基因中的遗传变异相关联。 设计：病例对照研究。 参与者：前瞻性招募了 197 名确诊的 AMD 患者和 150 名年龄匹配的无影响对照者参加该研究。 方法：在血清或血浆中分析溶血补体测定法（AP50、CP50 和 LP50）、补体成分（C3、CFB、CFI 和 CFH）和激活产物（C3d、C5a 和 SC5b-9）。对 DNA 样本进行了 5 个单核苷酸多态性（SNP）的基因分型，这些 SNP 先前与 CFH、ARMS2、C3、CFB 和 CFI 基因中的 AMD 相关联。 主要观察指标：补体浓度及其与 CFH、ARMS2、C3、CFB 和 CFI 基因中 SNP 的关联。 结果：AMD 患者的替代补体途径的激活增加（P = 0.003），补体激活成分 C3d（P<0.0001）和 C5a（P<0.0001）、CFB（P<0.0001）和 C3d/C3 比值升高（P<0.0001），作为 C3 激活的衡量标准。虽然 CFH 风险基因型与获得的升高的 C3d/C3 比值显著相关，但在不存在 CFH 风险等位基因的情况下，ARMS2 风险基因型也显示出显著升高的补体激活水平（P = 0.013）。此外，CFB 保护性等位基因的携带者 CFB 浓度较低。 结论：本研究发现的证据表明，在 AMD 中，CFH 和 ARMS2 的风险等位基因独立与补体激活相关联。特别是 C3d/C3 比值似乎是 AMD 的一个强有力的标志物。这些发现表明 CFH 和 ARMS2 在 AMD 的发病机制中具有共同的途径。
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