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Factor H-Related Protein 4 (FHR-4) drives complement dysregulation in age-related macular degeneration

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Abstract Number: 3870

AuthorBlock: Valentina Cipriani1,2, Laura Lorés de Motta3, Fan He4, Dina Fathalla5, Selina McHarg4, Nadhim Bayatti4, Ilhan Erkin Acar3, Carel C B Hoyng3, Sascha Fauser6,7, Anthony Moore2,8, John RW Yates2,9, Paul Morgan5, Eiko de Jong3, Anneke I. Den Hollander3,10, Paul N. Bishop4,11, Simon J. Clark4
1Queen Mary University of London, William Harvey Heart Centre, London, United Kingdom; 2UCL Institute of Ophthalmology, University College London, London, United Kingdom; 3Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands; 4Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom; 5Systems Immunity URI, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom; 6Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 7Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland; 8Ophthalmology Department, University of California San Francisco, San Francisco, California, United States; 9Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom; 10Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, Netherlands; 11Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, , United Kingdom;

DisclosureBlock: 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 C B Hoyng, None; Sascha Fauser, None; Anthony Moore, None; John RW Yates, None; Paul Morgan, None; Eiko de Jong, None; Anneke I. Den Hollander, None; Paul N. Bishop, None; Simon J. Clark, None;

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.

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