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Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration.

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Cipriani, Valentina  ORCID logo
Lorés-Motta, Laura 
Tilakaratna, Viranga 


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 = 7.1 × 10-6), 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 = 2.2 × 10-56), 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.


Funder: V.C. was primarily funded by the Department of Health’s NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology, and an MRC research grant (MR/P025838/1)


Aged, Apolipoproteins, Capillaries, Case-Control Studies, Complement Activation, Complement Factor H, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins, Liver, Macular Degeneration, Muscle Proteins, Polymorphism, Single Nucleotide, Retina

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Nat Commun

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Springer Science and Business Media LLC