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• W3004885588 abstract "Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10-6), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10-56), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD." @default.
• W3004885588 created "2020-02-14" @default.
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• W3004885588 date "2020-02-07" @default.
• W3004885588 modified "2023-10-15" @default.
• W3004885588 title "Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration" @default.
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• W3004885588 doi "https://doi.org/10.1038/s41467-020-14499-3" @default.
• W3004885588 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7005798" @default.
• W3004885588 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32034129" @default.
• W3004885588 hasPublicationYear "2020" @default.
• W3004885588 type Work @default.
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