Cipriani, Valentina ORCID: 0000-0002-0839-9955, Lores-Motta, Laura, He, Fan, Fathalla, Dina, Tilakaratna, Viranga, McHarg, Selina, Bayatti, Nadhim, Acar, Ilhan 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. and Clark, Simon J. (2020). Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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=7.1x10(-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=2.2x10(-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Cipriani, ValentinaUNSPECIFIEDorcid.org/0000-0002-0839-9955UNSPECIFIED
Lores-Motta, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
He, FanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fathalla, DinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tilakaratna, VirangaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McHarg, SelinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bayatti, NadhimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Acar, Ilhan E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyng, Carel B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fauser, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moore, Anthony T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yates, John R. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jong, Eiko K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, B. PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
den Hollander, Anneke I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bishop, Paul N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clark, Simon J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-345242
DOI: 10.1038/s41467-020-14499-3
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COMPLEMENT FACTOR-H; GENOME-WIDE ASSOCIATION; RARE GENETIC-VARIANTS; ALTERNATIVE PATHWAY; PLASMA-LEVELS; RISK; CFH; ACTIVATION; EXPRESSION; POLYMORPHISMMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34524

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