Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p = 2.4 × 10−10; FHR-2, p = 6.0 × 10−10; FHR-3, p = 1.5 × 10−5; FHR-4, p = 1.3 × 10−3; FHR-5, p = 1.9 × 10−4) and FHL-1 (p = 4.9 × 10−4) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD.
Date Issued
2021-08-05
Date Acceptance
2021-05-27
Citation
American Journal of Human Genetics, 2021, 108 (8), pp.1385-1400
ISSN
0002-9297
Publisher
Cell Press
Start Page
1385
End Page
1400
Journal / Book Title
American Journal of Human Genetics
Volume
108
Issue
8
Copyright Statement
© 2021 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000682516900003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
COMPLEMENT FACTOR-H
GENOME-WIDE ASSOCIATION
BRUCHS MEMBRANE
RARE
CFH
DELETION
GWAS
COLOCALIZATION
POLYMORPHISM
ACTIVATION
Publication Status
Published
Date Publish Online
2021-07-13