biostudies-literatureZouache MAU.S. Department of Health & Human Services | NIH | National Eye InstituteNEI NIH HHSResearch to Prevent BlindnessAdditional funding from philanthropic donations to the Steele Center for Translational Medicine, John A. Moran Eye Center, University of Utah.443https://www.ebi.ac.uk/biostudies/studies/S-EPMC10781981biostudies-literatureUnknown15(1)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 iNature communicationsLevels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression.PMC10781981Unrestricted Grant to the Department of Ophthalmology & Visual Sciences, University of Utah.R24 EY017404R24EY017404Fleckenstein MLiu JSchmitz-Valckenberg SHageman GSWilliams BLSeager NACorsetti TThomas JZouache MAAnstadt RAHageman JLHubbard WCRichards BTPappas CMMatthews SfalseLevels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression.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 i2024-01-01T00:00:00Z2024 Jan2026-06-02T11:29:43.467Z2024-11-09T13:40:26.526ZS-EPMC107819813820001010.1038/s41467-023-44605-0