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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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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.
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.
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).
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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