July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Factor H-Related Protein 4 (FHR-4) drives complement dysregulation in age-related macular degeneration
Author Affiliations & Notes
  • Valentina Cipriani
    Queen Mary University of London, William Harvey Heart Centre, London, United Kingdom
    UCL Institute of Ophthalmology, University College London, London, United Kingdom
  • Laura Lorés de Motta
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands
  • Fan He
    Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
  • Dina Fathalla
    Systems Immunity URI, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
  • Selina McHarg
    Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
  • Nadhim Bayatti
    Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
  • Ilhan Erkin Acar
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands
  • Carel C B Hoyng
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands
  • Sascha Fauser
    Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
    Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland
  • Anthony Moore
    UCL Institute of Ophthalmology, University College London, London, United Kingdom
    Ophthalmology Department, University of California San Francisco, San Francisco, California, United States
  • John RW Yates
    UCL Institute of Ophthalmology, University College London, London, United Kingdom
    Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
  • Paul Morgan
    Systems Immunity URI, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
  • Eiko de Jong
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands
  • Anneke I Den Hollander
    Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands
  • Paul N Bishop
    Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
    Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom
  • Simon J Clark
    Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
  • Footnotes
    Commercial Relationships   Valentina Cipriani, None; Laura Lorés de Motta, None; Fan He, None; Dina Fathalla, None; Selina McHarg, None; Nadhim Bayatti, None; Ilhan Erkin Acar, None; Carel Hoyng, None; Sascha Fauser, None; Anthony Moore, None; John Yates, None; Paul Morgan, None; Eiko de Jong, None; Anneke Den Hollander, None; Paul Bishop, None; Simon Clark, None
  • Footnotes
    Support  MR/P025838/1; MRC G0000067; Vidi Innovational Research Award 016.096.309; ERC Grant Agreement n. 310644 MACULA; MR/K024418/1
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3870. doi:https://doi.org/
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    • Get Citation

      Valentina Cipriani, Laura Lorés de Motta, Fan He, Dina Fathalla, Selina McHarg, Nadhim Bayatti, Ilhan Erkin Acar, Carel C B Hoyng, Sascha Fauser, Anthony Moore, John RW Yates, Paul Morgan, Eiko de Jong, Anneke I Den Hollander, Paul N Bishop, Simon J Clark; Factor H-Related Protein 4 (FHR-4) drives complement dysregulation in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3870. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic studies reported strong associations at the CFH locus, with 8 variants across KCNT2, CFH, and CFHR1-5 independently associated with AMD. How these variants impact protein expression and function remains to be disentangled. A recent genome-wide association study (GWAS) identified an intronic variant in CFHR4 that associated with increased systemic complement activation and AMD risk (Lorés-Motta et al., Ophthalmology 2018). Furthermore, Strunz et al. (Sci Rep 2018) have recently reported that the top AMD-associated CFH variant rs10922109 is associated with altered CFHR4 expression in liver. Here we investigated whether FHR-4 directly impacts AMD pathogenesis.

Methods : Blood levels of FHR-4 and FH were measured in 484 AMD late cases and 522 controls from two independent cohorts (Cambridge and EUGENDA). Phenotyped human macular sections were stained for FHR-4 and C3b. Affinity measurements of FHR-4 binding to C3b were performed by surface plasmon resonance and C3b breakdown functional assays were used to investigate the role of FHR-4 on complement regulation. The association of FHR-4 and FH levels with the 8 AMD risk CFH locus variants (and corresponding haplotypes) was assessed; GWAS meta-analyses of FHR-4 and FH levels were additionally performed.

Results : Systemic FHR-4 levels were elevated in late AMD (P=5.3x10-6), whereas no significant difference was observed for FH levels. We showed that CFHR4 is not expressed in the eye, but FHR-4 protein accumulates in the choriocapillaris, Bruch’s membrane and drusen and, by competing with FH and FHL-1, causes complement over-activation at these sites. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 had the highest association with reduced FHR-4 levels (P=2.2x10-56). No locus other than CFH showed genome-wide significant association in our meta-analysis of FHR-4 levels. The CFH haplotype analysis revealed that the effect of rs10922109 is independent of the AMD-protective CFHR1-3 deletion; furthermore, FHR-4 confers protection even in those individuals that carry the high-risk allele of rs1061170 (Y402H).

Conclusions : We dissected the GWAS results for AMD at the CFH locus and identified FHR-4 as a novel key molecular player causing complement dysregulation in AMD. FHR-4 may represent a potential therapeutic target.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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