Sharon Eccles Steele Center for Translational Medicine, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT, USA.
Nat Commun. 2024 Jan 10;15(1):443. doi: 10.1038/s41467-023-44605-0.
Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch's membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.
补体系统替代途径（AP）的失调是年龄相关性黄斑变性（AMD）的一个重要原因，AMD 是全球范围内不可逆转视力丧失的主要原因。在这里，我们评估了肝脏产生的补体因子 H 相关蛋白 4（FHR-4）对 AMD 发病机制和进展的贡献。我们表明，血浆中和 AMD 相关病理学的主要部位——视网膜色素上皮/布鲁赫膜/脉络膜界面的 FHR-4 变异完全由三个独立的数量性状基因座（QTL）解释。使用由 14965 名对照和 20741 名病例组成的两个不同队列，我们确定 FHR-4 的独立 QTL 与与 AMD 相关的变异不同，并且 FHR-4 变异与疾病不独立相关。此外，在主要由 AP 失调驱动的疾病患者中，FHR-4 似乎不会影响 AMD 的进展过程。因此，调节 FHR-4 不太可能成为 AMD 的有效治疗策略。
