Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression

• Published in: Nature communications Vol. 15; no. 1; pp. 443 - 17
• Main Authors: Zouache, M. A., Richards, B. T., Pappas, C. M., Anstadt, R. A., Liu, J., Corsetti, T., Matthews, S., Seager, N. A., Schmitz-Valckenberg, S., Fleckenstein, M., Hubbard, W. C., Thomas, J., Hageman, J. L., Williams, B. L., Hageman, G. S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 45/43; 692/308/2056; 692/308/575; 692/699/3161/1626; 82/51; 82/80; Age; Age related diseases; Alternative pathway; Bruch Membrane; Choroid; Cognition; Complement; Complement factor H; Complement Factor H - genetics; Complement system; Epithelium; Eye diseases; Gene mapping; Humanities and Social Sciences; Humans; Macular degeneration; Macular Degeneration - genetics; Modulation; multidisciplinary; Pathophysiology; Proteins; Quantitative trait loci; Retinal pigment epithelium; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• 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. C omplement factor H-related 4 protein (FHR-4) has been implicated in the pathophysiology of age-related macular degeneration (AMD). Here, in contrast, the authors find that levels of FHR-4 in plasma or ocular tissue do not appear to influence susceptibility to AMD or its course of progression, questioning whether modulation of FHR-4 is likely to be an effective therapeutic strategy.