Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish.

Autor:	Waksmunski AR; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States.; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States., Miskimen K; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States., Song YE; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States., Grunin M; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States., Laux R; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States., Fuzzell D; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States., Fuzzell S; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States., Adams LD; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States., Caywood L; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States., Prough M; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States., Stambolian D; Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States., Scott WK; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States., Pericak-Vance MA; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States., Haines JL; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States.; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States.; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States.
Jazyk:	angličtina
Zdroj:	Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2022 Aug 02; Vol. 63 (9), pp. 8.
DOI:	10.1167/iovs.63.9.8
Abstrakt:	Purpose: Genetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated. Methods: We performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs. Results: We identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues. Conclusions: In total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.
Databáze:	MEDLINE
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