Repository logo
 

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

Published version
Peer-reviewed

Change log

Authors

Cipriani, Valentina  ORCID logo  https://orcid.org/0000-0002-0839-9955
Lorés-Motta, Laura 
Tilakaratna, Viranga 

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.

Description

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)

Keywords

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

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

11

Publisher

Springer Science and Business Media LLC