Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration
Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration
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DOI：
10.1038/s41467-020-14499-3
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发表时间：
2020-02-07
影响因子：
16.6
通讯作者：
Clark, Simon J.
中科院分区：
文献类型：
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作者：
Cipriani, Valentina;Lores-Motta, Laura;Clark, Simon J.
年龄相关性黄斑变性（AMD）是导致失明的主要原因。染色体1q31.3上包含补体因子H （CFH， FH）和CFH相关基因（CFHR1-5）的遗传变异是AMD易感性的主要决定因素，但其分子后果尚不清楚。本研究表明FHR-4在AMD发病机制中起着重要作用。我们发现，AMD患者全身FHR-4水平升高（p值=7.1x10(-6)），而FH患者则无差异。此外，FHR-4在绒毛膜、布鲁氏膜和细胞膜中积累，可以与FH/FHL-1竞争C3b结合，阻止fi介导的C3b裂解。至关重要的是，与amd相关的CFH位点变体rs10922109的保护性等位基因与FHR-4水平降低的相关性最高（p值=2.2x10(-56)），与amd保护性CFHR1-3缺失无关，甚至在携带rs1061170 （Y402H）高风险等位基因的个体中也是如此。我们的研究结果确定FHR-4是AMD补体失调的关键分子。
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value=7.1x10(-6)), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value=2.2x10(-56)), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.