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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2020
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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. |
format | Online Article Text |
id | pubmed-7211993 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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