Universität zu Köln

Thee, Eric F., Colijn, Johanna M., Cougnard-Gregoire, Audrey, Meester-Smoor, Magda A., Verzijden, Timo, Hoyng, Carel B., Fauser, Sascha, Hense, Hans -Werner, Silva, Rufino ORCID: 0000-0001-8676-0833, Creuzot-Garcher, Catherine, Ueffing, Marius, Delcourt, Cecile ORCID: 0000-0002-2099-0481, den Hollander, Anneke I. and Klaver, Caroline C. W. (2022). The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1 The EYE-RISK Consortium. Ophthalmology, 129 (7). S. 752 - 765. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1549-4713

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Abstract

Purpose: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium. Design: Pooled analysis of 4 case-control and 6 cohort studies. Participants: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium. Methods: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan-Meier analyses in population-based cohorts. Main Outcome Measures: Age-related macular degeneration features and stage. Results: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5-11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4-13.3), and of mixed late AMD was 12.2 (95% CI, 7.3-20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0-11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 mu m (OR, 1.2; 95% CI, 0.9-1.7), but risks increased significantly for soft drusen >= 125 mu m (OR, 2.1; 95% CI, 1.5-3.0), up to an OR of 7.2 (95% CI, 3.8-13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2-5.4); risks of other characteristics were not different. Conclusions: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV. (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Thee, Eric F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Colijn, Johanna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cougnard-Gregoire, Audrey UNSPECIFIED UNSPECIFIED UNSPECIFIED Meester-Smoor, Magda A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Verzijden, Timo UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyng, Carel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hense, Hans -Werner UNSPECIFIED UNSPECIFIED UNSPECIFIED Silva, Rufino UNSPECIFIED orcid.org/0000-0001-8676-0833 UNSPECIFIED Creuzot-Garcher, Catherine UNSPECIFIED UNSPECIFIED UNSPECIFIED Ueffing, Marius UNSPECIFIED UNSPECIFIED UNSPECIFIED Delcourt, Cecile UNSPECIFIED orcid.org/0000-0002-2099-0481 UNSPECIFIED den Hollander, Anneke I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaver, Caroline C. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-694649
DOI:	10.1016/j.ophtha.2022.02.026
Journal or Publication Title:	Ophthalmology
Volume:	129
Number:	7
Page Range:	S. 752 - 765
Date:	2022
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1549-4713
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GEOGRAPHIC ATROPHY SECONDARY; 10Q26 LOCUS; HTRA1; ASSOCIATION; PROGRESSION; LOC387715; DISEASE; ARMS2; SUSCEPTIBILITY; POLYMORPHISM Multiple languages Ophthalmology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69464