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

Valentina Cipriani (), Laura Lorés-Motta, Fan He, Dina Fathalla, Viranga Tilakaratna, Selina McHarg, Nadhim Bayatti, İlhan E. Acar, Carel B. Hoyng, Sascha Fauser, Anthony T. Moore, John R. W. Yates, Eiko K. de Jong, B. Paul Morgan, Anneke I. den Hollander, Paul N. Bishop and Simon J. Clark ()
Additional contact information
Valentina Cipriani: Queen Mary University of London
Laura Lorés-Motta: Radboud University Medical Center
Fan He: University of Manchester
Dina Fathalla: Cardiff University
Viranga Tilakaratna: University of Manchester
Selina McHarg: University of Manchester
Nadhim Bayatti: University of Manchester
İlhan E. Acar: Radboud University Medical Center
Carel B. Hoyng: Radboud University Medical Center
Sascha Fauser: University Hospital of Cologne
Anthony T. Moore: University College London
John R. W. Yates: University College London
Eiko K. de Jong: Radboud University Medical Center
B. Paul Morgan: Cardiff University
Anneke I. den Hollander: Radboud University Medical Center
Paul N. Bishop: University of Manchester
Simon J. Clark: University of Manchester

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14499-3

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