TY - JOUR
T1 - Beyond factor H
T2 - The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations
AU - Cipriani, Valentina
AU - Tierney, Anna
AU - Griffiths, John
AU - Zuber, Verena
AU - Sergouniotis, Panos
AU - Yates, John R. W.
AU - Moore, Anthony T.
AU - Bishop, Paul
AU - Clark, Simon
AU - Unwin, Richard
N1 - Funding Information:
We are grateful to all the subjects who kindly participated in this research. For the Cambridge AMD Study ( UK Medical Research Council 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. We are grateful to Dr. Serena Sanna for the helpful discussion about causality and Mendelian-randomization analysis. We also thank the IAMDGC (for a full list of consortium members, please see the supplemental information ) for providing the genotype data for the Cambridge AMD study samples and the consortium summary association statistics for the two-sample Mendelian-randomization analysis. The Cambridge samples were genotyped as part of the IAMDGC exomechip project supported by Centre for Inherited Disease Research in Baltimore, MD (contract number HHSN268201200008I ) and funded by EY022310 (to J.L. Haines, Case Western Reserve University, Cleveland) and 1x01HG006934-01 (to G.R. Abecasis, University of Michigan, Department of Biostatistics). This work was funded by the Medical Research Council ( MR/P025838/1 ) and facilitated by the Manchester National Institute for Health Research Biomedical Research Centre and the Greater Manchester Comprehensive Local Research Network. The Stoller Biomarker Discovery Centre was established with an award from the Medical Research Council ( MR/M008959/1 ). S.J.C. is funded by the Helmut Ecker Foundation, Germany. The funding bodies had no role in the design of the study, in the collection, analysis, or interpretation of data, or in writing the manuscript.
Funding Information:
The mass-spectrometry data are available via the ProteomeXchange data repository under accession number PXD023466. The Genotype-Tissue Expression (GTEx) Project 46 dataset used for the gene expression analyses was obtained from the GTEx portal, dataset dbGaP accession number dbGaP: phs000424.v8.p2 (GTEx Analysis Release V8); 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.
Funding Information:
We are grateful to all the subjects who kindly participated in this research. For the Cambridge AMD Study (UK Medical Research Council 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. We are grateful to Dr. Serena Sanna for the helpful discussion about causality and Mendelian-randomization analysis. We also thank the IAMDGC (for a full list of consortium members, please see the supplemental information) for providing the genotype data for the Cambridge AMD study samples and the consortium summary association statistics for the two-sample Mendelian-randomization analysis. The Cambridge samples were genotyped as part of the IAMDGC exomechip project supported by Centre for Inherited Disease Research in Baltimore, MD (contract number HHSN268201200008I) and funded by EY022310 (to J.L. Haines, Case Western Reserve University, Cleveland) and 1x01HG006934-01 (to G.R. Abecasis, University of Michigan, Department of Biostatistics). This work was funded by the Medical Research Council (MR/P025838/1) and facilitated by the Manchester National Institute for Health Research Biomedical Research Centre and the Greater Manchester Comprehensive Local Research Network. The Stoller Biomarker Discovery Centre was established with an award from the Medical Research Council (MR/M008959/1). S.J.C. is funded by the Helmut Ecker Foundation, Germany. The funding bodies had no role in the design of the study, in the collection, analysis, or interpretation of data, or in writing the manuscript. P.N.B. S.J.C. and R.D.U. are inventors named in patent applications that describe the use of complement inhibitors for therapeutic purposes and the use of circulating complement-protein measurement for patient stratification and are co-founders of and shareholders in Complement Therapeutics, a company that focuses on the development of complement-targeted therapeutics, including for AMD. The remaining authors declare no competing interests.
Publisher Copyright:
© 2021 The Authors
PY - 2021/7/13
Y1 - 2021/7/13
N2 - Age-related macular degeneration (AMD) is a leading cause of vision loss, with a 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 the influence of AMD associated variants at this locus on FHL- 1 and FHR protein levels. We have used a bespoke targeted mass spectrometry assay to measure the circulating levels of all seven complement regulators, and demonstrated elevated levels in 352 advanced AMD individuals for all FHR proteins (FHR-1, P=2.4x10-10; FHR-2, P=6.0x10-10; FHR-3, P=1.5x10-5; FHR-4, P=1.3x10-3; FHR-5, P=1.9x10-4) and FHL-1 (P=4.9x10-4) compared to 252 controls, while 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 geneticallydriven 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.
AB - Age-related macular degeneration (AMD) is a leading cause of vision loss, with a 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 the influence of AMD associated variants at this locus on FHL- 1 and FHR protein levels. We have used a bespoke targeted mass spectrometry assay to measure the circulating levels of all seven complement regulators, and demonstrated elevated levels in 352 advanced AMD individuals for all FHR proteins (FHR-1, P=2.4x10-10; FHR-2, P=6.0x10-10; FHR-3, P=1.5x10-5; FHR-4, P=1.3x10-3; FHR-5, P=1.9x10-4) and FHL-1 (P=4.9x10-4) compared to 252 controls, while 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 geneticallydriven 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.
KW - Mendelian randomization
KW - age-related macular degeneration
KW - complement factor H
KW - factor H-related
KW - mass spectrometry
UR - http://www.scopus.com/inward/record.url?scp=85111566003&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/49cafb48-0a36-36f4-9a52-09be171eac51/
U2 - 10.1016/j.ajhg.2021.05.015
DO - 10.1016/j.ajhg.2021.05.015
M3 - Article
C2 - 34260948
VL - 108
SP - 1385
EP - 1400
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 8
ER -