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

Author

Listed:
  • Valentina Cipriani

    (Queen Mary University of London
    University College London
    Moorfields Eye Hospital NHS Foundation Trust
    University College 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
    Roche Pharma Research and Early Development)

  • Anthony T. Moore

    (University College London
    Moorfields Eye Hospital NHS Foundation Trust
    University of California San Francisco)

  • John R. W. Yates

    (University College London
    Moorfields Eye Hospital NHS Foundation Trust
    University of Cambridge)

  • Eiko K. de Jong

    (Radboud University Medical Center)

  • B. Paul Morgan

    (Cardiff University)

  • Anneke I. den Hollander

    (Radboud University Medical Center
    Radboud University Medical Centre)

  • Paul N. Bishop

    (University of Manchester
    Manchester Academic Health Science Centre)

  • Simon J. Clark

    (University of Manchester
    University of Manchester
    Eberhard Karls University of Tübingen)

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.

Suggested Citation

  • 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. , 2020. "Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14499-3
    DOI: 10.1038/s41467-020-14499-3
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    Cited by:

    1. M. A. Zouache & B. T. Richards & C. M. Pappas & R. A. Anstadt & J. Liu & T. Corsetti & S. Matthews & N. A. Seager & S. Schmitz-Valckenberg & M. Fleckenstein & W. C. Hubbard & J. Thomas & J. L. Hageman, 2024. "Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Valur Emilsson & Elias F. Gudmundsson & Thorarinn Jonmundsson & Brynjolfur G. Jonsson & Michael Twarog & Valborg Gudmundsdottir & Zhiguang Li & Nancy Finkel & Stephen Poor & Xin Liu & Robert Esterberg, 2022. "A proteogenomic signature of age-related macular degeneration in blood," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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