Loss of CFHR5 function reduces the risk for age-related macular degeneration.

Autor:	Reeve MP; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Loomis S; Research and Development, Biogen Inc., Cambridge, MA, USA., Nissilä E; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland., Rausch T; European Molecular Biological Laboratories (EMBL), Heidelberg, Germany., Zheng Z; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Briotta Parolo PD; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Ben-Isvy D; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA., Aho E; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland., Cesetti E; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.; Department of Biomedical Sciences, Humanitas University, Milan, Italy., Okunuki Y; Research and Development, Biogen Inc., Cambridge, MA, USA., McLaughlin H; Research and Development, Biogen Inc., Cambridge, MA, USA., Mäkelä J; Finnish Biobank Cooperative (FinBB), Turku, Finland., Kurki M; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Talkowski ME; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Korbel JO; European Molecular Biological Laboratories (EMBL), Heidelberg, Germany., Connor K; Research and Development, Biogen Inc., Cambridge, MA, USA., Meri S; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland., Daly MJ; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Runz H; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Research and Development, Biogen Inc., Cambridge, MA, USA.; European Molecular Biological Laboratories (EMBL), Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Nov 11. Date of Electronic Publication: 2024 Nov 11.
DOI:	10.1101/2024.11.11.24317117
Abstrakt:	Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene ( CFH ) is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four major CFH haplotypes that convey protection from AMD. We show that beyond CFH , two of these are explained by Finn-enriched frameshift and missense variants in the CFH modulator CFHR5 . We demonstrate through a FinnGen sample recall study that CFHR5 variant carriers exhibit dose-dependent reductions in serum levels of the CFHR5 gene product FHR-5 and two functionally related proteins at the locus. Genetic reduction in FHR-5 correlates with higher preserved activities of the classical and alternative complement pathways. Our results propose therapeutic downregulation of FHR-5 as promising to prevent or treat AMD. Competing Interests: Competing interests SL, YO, HML, KC and HR were employees at Biogen during data generation for this study. SL is an employee of Bristol-Myers Squibb. YO and KC are employees of Johnson & Johnson. HML is an employee of Moderna. JM is an employee of FinBB. MD is a co-founder of Maze Therapeutics. HR is an employee at insitro Inc. The other authors declare no competing interests.
Databáze:	MEDLINE
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