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Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating

Valentina Cipriani1, Anna Tierney2, John R Griffiths2

  • 1William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom; UCL Institute of Ophthalmology, University College London, London, EC1V 9EL, United Kingdom; Moorfields Eye Hospital National Health Service Foundation Trust, London, EC1V 2PD, United Kingdom; UCL Genetics Institute, University College London, London, WC1E 6BT, United Kingdom.

American Journal of Human Genetics
|July 14, 2021
PubMed

Insights

Elevated levels of factor H-related (FHR) proteins, but not factor H (FH), are linked to age-related macular degeneration (AMD). Genetic analysis confirms FHR proteins are key drivers of AMD susceptibility, suggesting FHR modulation as a potential therapy.

Area of Science:

  • Genetics and Immunology
  • Ophthalmology
  • Proteomics

Background:

  • Age-related macular degeneration (AMD) is a primary cause of vision loss with significant genetic links to the complement factor H (CFH) locus.
  • The CFH locus encodes complement regulators, including factor H (FH), factor-H-like 1 (FHL-1), and factor H-related proteins (FHR-1 to FHR-5), crucial for regulating complement factor C3b turnover.
  • The precise impact of AMD-associated variants on FHL-1 and FHR protein concentrations remains largely uncharacterized.

Purpose of the Study:

  • To quantify circulating concentrations of all seven complement regulators encoded by the CFH locus.
  • To investigate the association between AMD and the concentrations of these complement regulators.
  • To explore the genetic underpinnings of the relationship between CFH locus variants, FHR proteins, and AMD susceptibility.

Main Methods:

  • A targeted mass-spectrometry assay was developed to measure circulating levels of FH, FHL-1, and FHR-1 to FHR-5.
  • Concentrations were compared between 352 individuals with advanced AMD and 252 controls.
  • Genome-wide association analyses and Mendelian-randomization analyses were performed to assess genetic associations.

Main Results:

  • Significantly elevated concentrations of all FHR proteins (FHR-1 to FHR-5) and FHL-1 were observed in individuals with advanced AMD compared to controls.
  • No significant difference in FH concentrations was found between AMD patients and controls.
  • Genome-wide association studies identified significant signals at the CFH locus for all FHR proteins, and Mendelian-randomization supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility.

Conclusions:

  • Genetically driven alterations in circulating FHR proteins are strongly implicated as major contributors to AMD pathogenesis.
  • The study provides a biochemical basis for the genetic susceptibility to AMD linked to the CFH locus.
  • Targeting FHR protein modulation presents a promising therapeutic strategy for AMD.

Keywords:
Mendelian randomizationage-related macular degenerationcomplement factor Hfactor H-relatedmass spectrometry

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