gms | German Medical Science

7th International Symposium on AMD: Age-related Macular Degeneration – Understanding Pathogenetic Mechanisms of Disease

20.09. - 21.09.2019, Baden-Baden

Factor H-Related Protein 4 (FHR-4) drives complement dysregulation in AMD

Meeting Abstract

  • Laura Lorés de Motta - Nijmegen/NL
  • V. Cipriani - Queen Mary University of London, William Harvey Heart Centre, London/GB; London/GB
  • F. He - Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester/GB
  • D. Fathalla - Systems Immunity URI, Division of Infection and Immunity, School of Medicine, University of Cardiff/GB
  • S. McHarg - Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester/GB
  • N. Bayatti - Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester/GB
  • I.E. Acar - Nijmegen/NL
  • C.C.B. Hoyng - Nijmegen/NL
  • S. Fauser - Köln/D; Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel/CH
  • A. Moore - London/GB; San Francisco/USA
  • J.R.W. Yates - London/GB; Department of Medical Genetics, University of Cambridge/GB
  • P. Morgan - Systems Immunity URI, Division of Infection and Immunity, School of Medicine, University of Cardiff/GB
  • E.K. de Jong - Nijmegen/NL
  • A.I. den Hollander - Nijmegen/NL; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen/NL
  • P.N. Bishop - Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester/GB; Manchester/GB
  • S.J. Clark - Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester/GB

7th International Symposium on AMD: Age-related Macular Degeneration - Understanding Pathogenetic Mechanisms of Disease. Baden-Baden, 20.-21.09.2019. Düsseldorf: German Medical Science GMS Publishing House; 2020. Doc19amd16

doi: 10.3205/19amd16, urn:nbn:de:0183-19amd167

Veröffentlicht: 5. Februar 2020

© 2020 Lorés de Motta et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Background: Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic studies reported strong associations at the CFH locus, with 8 independent signals across KCNT2, CFH, and CFHR1-5. How these variants impact protein expression and function remains to be disentangled. Recently, a variant in CFHR4 which associates with increased systemic complement activation and AMD risk was identified (Lorés-Motta et al., Ophthalmology 2018). Here we investigated whether FHR-4 directly impacts AMD pathogenesis.

Methods: Blood levels of FHR-4 and FH were measured in 484 late AMD 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 and C3b breakdown functional assays were performed. Association of FHR-4 and FH levels with the 8 AMD-associated variants at the CFH locus (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. CFHR4 was not expressed in the eye, but FHR-4 protein accumulated 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. 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.