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A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes

Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like prote...

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Autores principales: Alic, Lejla, Papac-Milicevic, Nikolina, Czamara, Darina, Rudnick, Ramona B., Ozsvar-Kozma, Maria, Hartmann, Andrea, Gurbisz, Michael, Hoermann, Gregor, Haslinger-Hutter, Stefanie, Zipfel, Peter F., Skerka, Christine, Binder, Elisabeth B., Binder, Christoph J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211993/
https://www.ncbi.nlm.nih.gov/pubmed/32321835
http://dx.doi.org/10.1073/pnas.1913970117
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author Alic, Lejla
Papac-Milicevic, Nikolina
Czamara, Darina
Rudnick, Ramona B.
Ozsvar-Kozma, Maria
Hartmann, Andrea
Gurbisz, Michael
Hoermann, Gregor
Haslinger-Hutter, Stefanie
Zipfel, Peter F.
Skerka, Christine
Binder, Elisabeth B.
Binder, Christoph J.
author_facet Alic, Lejla
Papac-Milicevic, Nikolina
Czamara, Darina
Rudnick, Ramona B.
Ozsvar-Kozma, Maria
Hartmann, Andrea
Gurbisz, Michael
Hoermann, Gregor
Haslinger-Hutter, Stefanie
Zipfel, Peter F.
Skerka, Christine
Binder, Elisabeth B.
Binder, Christoph J.
author_sort Alic, Lejla
collection PubMed
description Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.
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spelling pubmed-72119932020-05-15 A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes Alic, Lejla Papac-Milicevic, Nikolina Czamara, Darina Rudnick, Ramona B. Ozsvar-Kozma, Maria Hartmann, Andrea Gurbisz, Michael Hoermann, Gregor Haslinger-Hutter, Stefanie Zipfel, Peter F. Skerka, Christine Binder, Elisabeth B. Binder, Christoph J. Proc Natl Acad Sci U S A Biological Sciences Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis. National Academy of Sciences 2020-05-05 2020-04-22 /pmc/articles/PMC7211993/ /pubmed/32321835 http://dx.doi.org/10.1073/pnas.1913970117 Text en Copyright © 2020 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Alic, Lejla
Papac-Milicevic, Nikolina
Czamara, Darina
Rudnick, Ramona B.
Ozsvar-Kozma, Maria
Hartmann, Andrea
Gurbisz, Michael
Hoermann, Gregor
Haslinger-Hutter, Stefanie
Zipfel, Peter F.
Skerka, Christine
Binder, Elisabeth B.
Binder, Christoph J.
A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes
title A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes
title_full A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes
title_fullStr A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes
title_full_unstemmed A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes
title_short A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes
title_sort genome-wide association study identifies key modulators of complement factor h binding to malondialdehyde-epitopes
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211993/
https://www.ncbi.nlm.nih.gov/pubmed/32321835
http://dx.doi.org/10.1073/pnas.1913970117
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