Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration
View / Open Files
Hoyng, Carel B.
Moore, Anthony T.
Yates, John R. W.
Morgan, B. Paul
Bishop, Paul N.
Nature Publishing Group UK
MetadataShow full item record
Cipriani, V., Lorés-Motta, L., He, F., Fathalla, D., Tilakaratna, V., McHarg, S., Bayatti, N., et al. (2020). Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration. Nature Communications, 11 (1)https://doi.org/10.1038/s41467-020-14499-3
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)
Abstract: 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.
Article, /631/45, /631/208/205, /631/250, /692/53, /692/699/3161, /45/43, /13/51, /82/103, /82/1, article
External DOI: https://doi.org/10.1038/s41467-020-14499-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/317271
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/