Critical Dependence on Area in Relationship between ARMS2/HTRA1 Genotype and Faster Geographic Atrophy Enlargement: AREDS2 Report 33.

PURPOSE: To analyze ARMS2/HTRA1 as a risk factor for faster geographic atrophy (GA) enlargement according to (i) GA area and (ii) contiguous enlargement versus progression to multifocality.

DESIGN: Post hoc analysis of a cohort within the Age-Related Eye Disease Study 2 (AREDS2) clinical trial.

PARTICIPANTS: 546 eyes (406 participants, mean age 73.8 years) with GA.

METHODS: GA area was measured from color fundus photographs at annual visits. Mixed-model regression of square root GA area, and proportional hazards regression of progression to multifocal GA, were analyzed according to ARMS2 genotype.

MAIN OUTCOME MEASURES: (i) change in square root GA area; (ii) progression to multifocal GA.

RESULTS: GA enlargement was significantly faster in eyes with ARMS2 risk alleles (P<0.0001), at 0.224 mm/year (95% CI 0.195-0.252), 0.298 (0.271-0.324), and 0.317 (0.279-0.355), for 0-2 risk alleles, respectively. However, a significant interaction (P=0.011) was observed between genotype and baseline GA area. In eyes with very small GA area (<1.9 mm2 ), enlargement was significantly faster with ARMS2 risk alleles (P<0.0001), at 0.193 mm/year (0.162-0.225) versus 0.304 (0.280-0.329), for 0 versus 1-2 risk alleles, respectively. In eyes with moderately small (1.9-3.8 mm2 ) or medium/large (≥3.8 mm2 ) GA area, enlargement was not significantly faster with ARMS2 risk alleles (P=0.66 and P=0.70, respectively). In eyes with non-multifocal GA, enlargement was significantly faster with ARMS2 risk alleles (P=0.001), at 0.175 mm/year (0.142-0.209), 0.226 (0.193-0.259), and 0.287 (0.237-0.337), with 0-2 risk alleles, respectively. ARMS2 genotype was not significantly associated with progression to multifocal GA; the hazard ratios for 1 and 2 risk alleles, respectively, were 1.03 (0.70-1.53; P=0.87) and 1.12 (0.67-1.88; P=0.66).

CONCLUSIONS: The relationship between ARMS2/HTRA1 genotype and faster GA enlargement depends critically on GA area: risk alleles represent a strong risk factor for faster enlargement only in eyes with very small GA area. They increase the growth rate more through contiguous enlargement than progression to multifocality. ARMS2/HTRA1 genotype is more important in increasing risk of progression to GA and initial GA enlargement (contiguously) than in subsequent enlargement or progression to multifocality. These findings may explain some discrepancies between previous studies and have implications for both research and clinical practice.