| Autor: |
Cipriani, Valentina, Lorés-Motta, Laura, He, Fan, Fathalla, Dina, Tilakaratna, Viranga, McHarg, Selina, Bayatti, Nadhim, Acar, İlhan E., Hoyng, Carel B., Fauser, Sascha, Moore, Anthony T., Yates, John R. W., de Jong, Eiko K., Morgan, B. Paul, den Hollander, Anneke I., Bishop, Paul N., Clark, Simon J. |
| Předmět: |
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| Zdroj: |
Nature Communications; 2/7/2020, Vol. 11 Issue 1, p1-15, 15p |
| Abstrakt: |
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. A locus on chromosome 1 encompassing the CFHR genes is highly associated with AMD risk. Here, Cipriani and colleagues investigate the role of CFHR4, encoding FHR-4, and demonstrate a relationship between AMD risk, circulating FHR-4 levels and genetic variants at this locus. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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