TY - JOUR
T1 - Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration
AU - Cipriani, Valentina
AU - Lores-Motta, Laura
AU - He, Fan
AU - Fathalla, Dina
AU - Tilakaratna, Viranga
AU - Mcharg, Selina
AU - Bayatti, Nadhim
AU - Acar, Ilhan E.
AU - Hyong, Carel B.
AU - Fauser, Sascha
AU - Moore, Anthony T.
AU - Yates, John R. W.
AU - de Jong, Eiko K.
AU - Morgan, B. Paul
AU - den Hollander, Anneke I.
AU - Bishop, Paul
AU - Clark, Simon
N1 - Funding Information:
The Gene Expression Omnibus datasets used for the gene expression analyses are: GSE18811; GSE41102; GSE50195; GSE94437; GSE99248. The Genotype-Tissue Expression (GTEx) Project datasets used for the gene expression analyses were obtained from the GTEx Portal, https://gtexportal.org/home/multiGeneQueryPage (4/4/2018), dataset dbGaP accession number phs000424.v8.p2; the GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The source data underlying Figs. 1, 2b–i, 3b, 4, 5a, 6a, b and Supplementary Figs. 2a, 5, 6, 7a–d, 8, 10a, 11 are provided as a Source Data file. All other datasets and reagents generated/used in the current study are available from the corresponding authors upon reasonable request.
Funding Information:
We are grateful to all the subjects who kindly participated in this research. For the Cambridge AMD Study (UK Medical Research Council (MRC) grant G0000067 to J.R.W.Y. and A.T.M.), we gratefully acknowledge help with patient recruitment from members of the Genetic Factors in AMD Study Group (P. Black, Z. Butt, V. Chong, C. Edelsten, A. Fitt, D.W. Flanagan, A. Glenn, S.P. Harding, C. Jakeman, C. Jones, R.J. Lamb, V. Moffatt, C.M. Moorman, R.J. Pushpanathan, E. Redmond, T. Rimmer and D.A. Thurlby); we thank Jane Khan and Humma Shahid for carrying out the clinical evaluation and sampling of subjects and Tunde Peto and colleagues at the Reading Centre, Moorfields Eye Hospital, London, for grading the fundus photographs. EUGENDA was funded by grants from the Oogfonds, MaculaFonds, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Blindenhulp, Stichting A.F. Deutman Oogheelkunde Research-fonds, the Netherlands Organization for Scientific Research (Vidi Innovational Research Award 016.096.309), and the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) (ERC Grant Agreement no. 310644 MACULA). We wish to thank the Manchester Eye Tissue Repository for supplying human macula tissue, and their funding from the Macular Society UK (12928). We also thank the IAMDGC (http://eaglep.case.edu/iamdgc_web/; for a full list of consortium members, please see Supplementary Note 1) for providing the genotype data. The Cambridge and EUGENDA samples were genotyped as part of the IAMDGC exome-chip project supported by CIDR (contract number HHSN268201200008I) and funded by EY022310 (to Jonathan L. Haines, Case Western Reserve University, Cleveland) and 1 × 01HG006934-01 (to Gonçalo R. Abecasis, University of Michigan, Department of Biostatistics). We wish to thank Lars Fritsche for providing CFH locus-phased genotype data for the IAMDGC primary analysis dataset. Other funding sources are as follows: S.J.C./V.T., an MRC fellowship (MR/K024418/1); S.M., Fight for Sight UK research grant (1517/1518); B.P.M./D.F. supported by a Programme Grant from the MRC-supported UK Dementia Research Institute; V.C. was primarily funded by the Department of Health’s NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology, and an MRC research grant (MR/ P025838/1). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/7
Y1 - 2020/2/7
N2 - Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the 39 chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes 40 (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences 41 remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. 42 We show that systemic FHR-4 levels are elevated in AMD (P-value=7.1x10-6), whereas no 43 difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch’s 44 membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated 45 C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant 46 rs10922109 has the highest association with reduced FHR-4 levels (P-value=2.2x10-56), 47 independently of the AMD-protective CFHR1–3 deletion, and even in those individuals that carry 48 the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player 49 contributing to complement dysregulation in AMD.
AB - Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the 39 chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes 40 (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences 41 remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. 42 We show that systemic FHR-4 levels are elevated in AMD (P-value=7.1x10-6), whereas no 43 difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch’s 44 membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated 45 C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant 46 rs10922109 has the highest association with reduced FHR-4 levels (P-value=2.2x10-56), 47 independently of the AMD-protective CFHR1–3 deletion, and even in those individuals that carry 48 the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player 49 contributing to complement dysregulation in AMD.
KW - Aged
KW - Apolipoproteins/blood
KW - Capillaries/metabolism
KW - Case-Control Studies
KW - Complement Activation
KW - Complement Factor H/metabolism
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Haplotypes
KW - Humans
KW - Intracellular Signaling Peptides and Proteins/metabolism
KW - LIM Domain Proteins/metabolism
KW - Liver/physiology
KW - Macular Degeneration/blood
KW - Muscle Proteins/metabolism
KW - Polymorphism, Single Nucleotide
KW - Retina/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85079084415&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14499-3
DO - 10.1038/s41467-020-14499-3
M3 - Article
C2 - 32034129
SN - 2041-1723
VL - 11
SP - 778
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 778
ER -