Artikel
Factor H-Related Protein 4 (FHR-4) drives complement dysregulation in AMD
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Veröffentlicht: | 5. Februar 2020 |
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Gliederung
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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.