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Abstract：
Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10-6), FHR-2 (p = 1.47 × 10-4), FHR-3 (p = 1.05 × 10-5) and FHR-4A (p = 1.22 × 10-2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10-17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10-3 and p = 2.81 × 10-6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10-16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
摘要：
年龄相关性黄斑变性（AMD）是老年人群失明的主要原因。据报道，CFH基因座的遗传变异对AMD风险有很大影响，包括补体因子H（CFH）和补体因子H相关（CFHR）基因，但是潜在的机制还没有完全理解。我们旨在在202名对照和216名AMD患者的队列中剖析H因子（FH）和FH相关（FHR）蛋白在AMD中的作用。我们检测到FHR-1的全身水平升高（p=1.84×10-6），FHR-2（p=1.47×10-4），AMD患者的FHR-3(p=1.05×10-5)和FHR-4A(p=1.22×10-2),而FH浓度保持不变。CFH位点的常见AMD遗传变异和单倍型与FHR蛋白浓度密切相关（例如，FHp.Tyr402His和FHR-2浓度，p=3.68×10-17)，而与FH浓度的关联有限。此外，在一个由17,596名对照和15,894名AMD患者组成的国际AMD基因组学联盟队列中，我们发现低频和罕见的蛋白改变性CFHR2和CFHR5变异与AMD相关,与之前报道的所有全基因组关联研究(GWAS)信号无关(分别为p=5.03×10-3和p=2.81×10-6).CFHR2和CFHR5中的低频变体导致FHR-2和FHR-5浓度降低或缺失（例如，CFHR2和FHR-2中的p.Cys72Tyr，p=2.46×10-16)。最后,我们显示了FHR-2和FHR-5在脉络膜绒毛膜疣和玻璃疣中的定位。我们的研究确定FHR蛋白是AMD疾病机制中的关键蛋白。因此,调节FHR蛋白的疗法可能对治疗或预防AMD的进展有效.这样的疗法可以基于他们在CFH基因座处的基因型靶向患有AMD的特定个体。
