TY - JOUR
T1 - Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration
AU - Lorés-Motta, Laura
AU - van Beek, Anna E.
AU - Willems, Esther
AU - Zandstra, Judith
AU - van Mierlo, Gerard
AU - Einhaus, Alfred
AU - Mary, Jean-Luc
AU - Stucki, Corinne
AU - Bakker, Bjorn
AU - Hoyng, Carel B.
AU - Fauser, Sascha
AU - Clark, Simon J.
AU - de Jonge, Marien I.
AU - Nogoceke, Everson
AU - Koertvely, Elod
AU - Jongerius, Ilse
AU - Kuijpers, Taco W.
AU - den Hollander, Anneke I.
N1 - Funding Information: This study was funded by the Roche Postdoctoral Fellowship Programme (RPF-ID 480). The study was partially supported by the European Union’s Seventh Framework program under EC-GA no. 279185 ( EUCLIDS ) and by the European Union Horizon 2020 research and innovation program under EC-GA no. 668303 ( PERFORM ). The EUGENDA cohort was funded by grants from the Oogfonds , MaculaFonds , Landelijke Stichting voor Blinden en Slechtzienden , Stichting Blindenhulp , Stichting A.F. Deutman Oogheelkunde Researchfonds , the Dutch Research Council (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). The EUGENDA samples were genotyped as part of the IAMDGC exome chip project supported by the Center for Inherited Disease Research (contract number HHSN268201200008I) and funded by EY022310 (to Jonathan L. Haines, Case Western Reserve University, Cleveland) and 1x01HG006934-01 (to Gonçalo R. Abecasis, University of Michigan, Department of Biostatistics). We would like to acknowledge the contribution of the International AMD Genomics Consortium (IAMDGC) for providing genotypes at the CFH locus from the IAMDGC dataset, and we thank Iris Heid and Thomas Winkler for aiding in the data extraction. We thank Tessel Galesloot for her critical revision of the manuscript. Funding Information: This study was funded by the Roche Postdoctoral Fellowship Programme (RPF-ID 480). The study was partially supported by the European Union's Seventh Framework program under EC-GA no. 279185 (EUCLIDS) and by the European Union Horizon 2020 research and innovation program under EC-GA no. 668303 (PERFORM). The EUGENDA cohort was funded by grants from the Oogfonds, MaculaFonds, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Blindenhulp, Stichting A.F. Deutman Oogheelkunde Researchfonds, the Dutch Research Council (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). The EUGENDA samples were genotyped as part of the IAMDGC exome chip project supported by the Center for Inherited Disease Research (contract number HHSN268201200008I) and funded by EY022310 (to Jonathan L. Haines, Case Western Reserve University, Cleveland) and 1x01HG006934-01 (to Gon?alo R. Abecasis, University of Michigan, Department of Biostatistics). We would like to acknowledge the contribution of the International AMD Genomics Consortium (IAMDGC) for providing genotypes at the CFH locus from the IAMDGC dataset, and we thank Iris Heid and Thomas Winkler for aiding in the data extraction. We thank Tessel Galesloot for her critical revision of the manuscript. Publisher Copyright: © 2021 The Author(s)
PY - 2021/8/5
Y1 - 2021/8/5
N2 - Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10−6), FHR-2 (p = 1.47 × 10−4), FHR-3 (p = 1.05 × 10−5) and FHR-4A (p = 1.22 × 10−2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10−17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10−3 and p = 2.81 × 10−6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10−16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
AB - Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10−6), FHR-2 (p = 1.47 × 10−4), FHR-3 (p = 1.05 × 10−5) and FHR-4A (p = 1.22 × 10−2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10−17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10−3 and p = 2.81 × 10−6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10−16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
KW - AMD
KW - CFH
KW - CFHR2
KW - CFHR5
KW - age-related macular degeneration
KW - complement Factor H
KW - complement system
KW - complement-factor-H-related
UR - http://www.scopus.com/inward/record.url?scp=85111578850&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2021.06.002
DO - https://doi.org/10.1016/j.ajhg.2021.06.002
M3 - Article
C2 - 34260947
SN - 0002-9297
VL - 108
SP - 1367
EP - 1384
JO - American journal of human genetics
JF - American journal of human genetics
IS - 8
ER -