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

Author:

Cipriani ValentinaORCID,Lorés-Motta Laura,He FanORCID,Fathalla DinaORCID,Tilakaratna Viranga,McHarg Selina,Bayatti Nadhim,Acar İlhan E.ORCID,Hoyng Carel B.,Fauser Sascha,Moore Anthony T.,Yates John R. W.,de Jong Eiko K.ORCID,Morgan B. Paul,den Hollander Anneke I.ORCID,Bishop Paul N.,Clark Simon J.ORCID

Abstract

AbstractAge-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

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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