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

Valentina Cipriani, Laura Lores-Motta, Fan He, Dina Fathalla, Viranga Tilakaratna, Selina Mcharg, Nadhim Bayatti, Ilhan E. Acar, Carel B. Hyong, Sascha Fauser, Anthony T. Moore, John R. W. Yates, Eiko K. de Jong, B. Paul Morgan, Anneke I. den Hollander, Paul Bishop, Simon Clark

Research output: Contribution to journalArticlepeer-review

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the 39 chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes 40 (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences 41 remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. 42 We show that systemic FHR-4 levels are elevated in AMD (P-value=7.1x10-6), whereas no 43 difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch’s 44 membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated 45 C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant 46 rs10922109 has the highest association with reduced FHR-4 levels (P-value=2.2x10-56), 47 independently of the AMD-protective CFHR1–3 deletion, and even in those individuals that carry 48 the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player 49 contributing to complement dysregulation in AMD.
Original languageEnglish
Article number778
Pages (from-to)778
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 7 Feb 2020

Keywords

  • Aged
  • Apolipoproteins/blood
  • Capillaries/metabolism
  • Case-Control Studies
  • Complement Activation
  • Complement Factor H/metabolism
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Intracellular Signaling Peptides and Proteins/metabolism
  • LIM Domain Proteins/metabolism
  • Liver/physiology
  • Macular Degeneration/blood
  • Muscle Proteins/metabolism
  • Polymorphism, Single Nucleotide
  • Retina/metabolism

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