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
Year: 2021
Type: article
Study design: Observational Study
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.
Authors: Valentina Cipriani, Anna Tierney, John R. Griffiths, Verena Zuber, Panagiotis I. Sergouniotis, John R.W. Yates, Anthony T. Moore, Paul N. Bishop, Simon J. Clark, Richard D. Unwin
Institutions: National Health Service, Moorfields Eye Hospital NHS Foundation Trust, Queen Mary University of London, William Harvey Research Institute, Moorfields Eye Hospital, University College London, University of Manchester, Imperial College London, St Mary's Hospital, University of Cambridge, University of California, San Francisco, Manchester Academic Health Science Centre, Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, University of Tübingen
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: National Institute for Health and Care Research, Moorfields Eye Hospital NHS Foundation Trust, National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Eye Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: G1036172374, G1556553536, G3226771441, G4369541769, G4407350458, Manchester Molecular Pathology Innovation Centre (MMPathIC): bridging the gap between biomarker discovery and health and wealth, Investigating the influence of genetic variation associated with age-related macular degeneration on plasma levels of complement regulatory proteins, Manchester Academic Health Science Centre Technology Hub: Clinical Proteomics Centre for Stratified Medicine, International Advancing genomics through the AMD Genomics Consortium (IAMDGC)
OpenAlex ID: W3180384136