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Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression

Author

Listed:
  • M. A. Zouache

    (University of Utah)

  • B. T. Richards

    (University of Utah)

  • C. M. Pappas

    (University of Utah)

  • R. A. Anstadt

    (University of Utah)

  • J. Liu

    (University of Utah)

  • T. Corsetti

    (University of Utah)

  • S. Matthews

    (University of Utah)

  • N. A. Seager

    (University of Utah)

  • S. Schmitz-Valckenberg

    (University of Utah)

  • M. Fleckenstein

    (University of Utah)

  • W. C. Hubbard

    (University of Utah)

  • J. Thomas

    (University of Utah)

  • J. L. Hageman

    (University of Utah)

  • B. L. Williams

    (University of Utah)

  • G. S. Hageman

    (University of Utah)

Abstract

Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch’s membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44605-0
    DOI: 10.1038/s41467-023-44605-0
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