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

Cipriani, Valentina, Lorés-Motta, Laura, He, Fan, Fathalla, Dina, Tilakaratna, Viranga, McHarg, Selina, Bayatti, Nadhim, Acar, İlhan E, Hoyng, Carel B, Fauser, Sascha, Moore, Anthony T, Yates, John RW, de Jong, Eiko K, Morgan, B Paul, den Hollander, Anneke I, Bishop, Paul N and Clark, Simon J 2020. Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration. Nature Communications 11 , 778. 10.1038/s41467-020-14499-3

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 5 February 2020
Date of Acceptance: 10 January 2020
Last Modified: 03 Sep 2020 01:22
URI: http://orca.cf.ac.uk/id/eprint/129352

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