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Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration
- Source :
- American Journal of Human Genetics, The American Journal of Human Genetics, American Journal of Human Genetics, 108, 8, pp. 1367-1384, American Journal of Human Genetics, 108, 1367-1384, Lorés-Motta, L, van Beek, A, Willems, E, Zandstra, J, van Mierlo, G, Einhaus, A, Mary, J-L, Stucki, C, Bakker, B, Hoyng, C, Fauser, S, Clark, S, de Jonge, M, Nogoceke, E, Koertvely, E, Jongerius, I, Kuijpers, T & den Hollander, A 2021, ' Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR levels and age-related macular degeneration ', Am J Hum Genet . https://doi.org/10.1016/j.ajhg.2021.06.002, American journal of human genetics, 108(8), 1367-1384. Cell Press
- Publication Year :
- 2020
-
Abstract
- 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 x 10(-6)), FHR-2 (p = 1.47 x 10(-4)), FHR-3 (p = 1.05 x 10(-5)) and FHR-4A (p = 1.22 x 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 x 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 x 10(-3) and p = 2.81 x 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 x 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.
- Subjects :
- CFHR5
genetic structures
CFHR2
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
Locus (genetics)
Genome-wide association study
Biology
Drusen
AMD
complement-factor-H-related
Polymorphism, Single Nucleotide
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Article
Cohort Studies
03 medical and health sciences
Macular Degeneration
All institutes and research themes of the Radboud University Medical Center
0302 clinical medicine
Genotype
Genetics
medicine
Complement C3b Inactivator Proteins
Humans
Genetic Predisposition to Disease
age-related macular degeneration
Genetics (clinical)
complement system
030304 developmental biology
0303 health sciences
complement Factor H
Haplotype
Complement System Proteins
Macular degeneration
medicine.disease
eye diseases
3. Good health
Haplotypes
Factor H
embryonic structures
030221 ophthalmology & optometry
CFH
sense organs
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 15376605 and 00029297
- Volume :
- 108
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- American journal of human genetics
- Accession number :
- edsair.doi.dedup.....ad3a920e528b8e45e1981b13be551973