Carriers of ARMS2/HTRA1 Locus Linked to High Risk of Late AMD at Early Age

Caroline C.W. Klaver, MD, PhD

New findings suggest that the risk variant at the age-related maculopathy susceptibility 2/ high-temperature requirement A serine peptidase 1 (ARMS2/HTRA-1) locus was associated with intermediate and late age-related macular degeneration (AMD) features.

Carriers of the homozygote were linked to a particularly high risk of late AMD at early age, according to investigators.

“Compared with other genetic variants, the ARMS2/HTRA1 risk variant showed a similar phenotypic pattern of AMD but also showed strikingly greater risks of the end stages at earlier ages,” wrote study author Caroline C.W. Klaver, MD, PhD, Department of Ophthalmology, Erasmus Medical Centre.

The locus carrying the highest risk is age-related maculopathy susceptibility 2 (ARMS2), but its biological function is still under investigation for AMD. There are still uncertainties on the phenotypic differences between carriers of the ARMS2/HTRA-1 risk variant and those with risk in complement genes.

In a large dataset of the European Eye Epidemiology and EYE-RISK Consortia, the investigators set out to determine the full range of AMD characteristics associated with the risk haplotype at ARMS2/HTRA1 and with variants at the complement pathway. The design was a pooled analysis of 4 case-control and 6 cohort studies.

A total of 17,204 participants had gradable fundus photographs, genotype information for the ARMS2/HTRA1 risk variants, and a baseline age of 55 years or older. They determined AMD features and macular thickness on multimodal images, while data on genetics and phenotype were harmonized.

Additionally, the risks of AMD features for genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score of 19 variants at the complement pathway. Investigators estimated lifetime risks with Kaplan-Meier analyses in population-based cohorts.

Out of 2068 individuals identified with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. Meanwhile, for homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5 - 11.4) and of choroidal neovascularization was 11.2 (95% CI, 9.4 - 13.3), as well as 12.2 for mixed late AMD (95% CI, 7.3 - 20.6).

The cumulative lifetime risk of late AMD had a range of 4.4% for carriers of the non risk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. Investigators noted the latter patients received the diagnosis of late AMD 9.6 years (95% CI, 8.0 - 11.2) earlier than carriers of the non risk genotype.

Data show the risk haplotype was not associated with hard or soft drusen <125 μm, (OR, 1.2; 95% CI, 0.9 - 1.7), but the 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.

In comparison to individuals with a high genetic risk score, homozygous carriers of ARMS2/HTRA1 had a higher risk of choroidal neovascularization (OR, 4.1; 95% CI, 3.2 - 5.4). However, the risks of other characteristics were not different, investigators found.

“More in-depth investigation into the biological properties of ARMS2/HTRA1 will be a significant step toward unraveling AMD pathogenesis,” Klaver concluded.

The study, “The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The Eye-Risk Consortium,” was published in Ophthalmology.