The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium.
Ophthalmology
; 129(7): 752-764, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-35240203
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 OUTCOMEMEASURES:
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 µm (OR, 1.2; 95% CI, 0.9-1.7), but risks increased significantly for soft drusen ≥ 125 µm (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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Drusas Retinianas
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Neovascularização de Coroide
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Degeneração Macular
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Observational_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article