The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium

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English. ABSTRACT Purpose 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 ARMS2/HTRA1 in a large European consortium. Design Pooled analysis of 4 case-control and 6 cohort studies Participants Ten studies from the European Eye Epidemiology consortium provided data on 17,204 individuals aged 55+ years Methods AMD 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 compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan Meier product-limit analyses in prospective population-based cohorts. Main Outcome Measures AMD 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%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 life-time risk of late AMD ranged from 4.4% for carriers of the non-risk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers, respectively. The latter received the diagnosis of late AMD 9.6 (95%CI 8.0–11.2) years earlier than carriers of the non-risk genotype. The risk haplotype was not associated with hard or soft distinct drusen <125um (OR 1.2, 95% 0.9–1.7), but risks increased significantly for soft indistinct drusen ≥125um (OR 2.1, 95%CI 1.5-3.0), up to OR 7.2 (95% CI 3.8–13.8) for reticular pseudodrusen. Compared to persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 had a significantly higher risk of CNV (OR 4.1, 95%CI 3.2–5.4); risks of other characteristics including macular thickness were not significantly different. Conclusions Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Our 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.