GENOTYPE-PHENOTYPE ASSOCIATIONS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION

Purpose: To examine associations between recognized genetic susceptibility loci and angiographic subphenotypes of the neovascular variant of age-related macular degeneration (nvAMD). Methods: Participants (247 nvAMD, 52 early age-related macular degeneration [AMD], and 103 controls) were genotyped (complement factor H and ARMS2/HTRA1). nvAMD participants were assigned to one of two subcategories: mainly classic or mainly occult (based on the proportions of classic and occult choroidal neovascularization). nvAMD and early AMD were reassigned to two groups based on the extent and severity of drusen (retinal pigment epithelium dysfunction or not). Univariate and multivariate analysis were used to examine for associations between participant characteristics and genetic loci after adjusting for age, smoking status, and history of cardiovascular disease. Results: Univariate analysis confirmed the known significant associations between AMD stage and age, hypertension, and a history of cardiovascular disease. Those with retinal pigment epithelium dysfunction (F = 5.46; P = 0.02) or a positive smoking history (F = 3.89; P = 0.05) were more likely to have been classified as having mainly an occult rather than a mainly classic lesion. Multivariate analysis showed that significant associations were noted with the number of ARMS2/HTRA1 risk alleles (P < 0.001), smoking (ever vs. never) (P = 0.03), and cardiovascular disease (P = 0.01). With early AMD as the reference category, the mainly classic group exhibited significant associations with the number of ARMS2/HTRA1 risk alleles present (P < 0.001) and cardiovascular disease (P = 0.02). When mainly classic was compared with mainly occult, the latter was associated with the ARMS2/HTRA1 locus (P = 0.02). Conclusion: ARMS2/HTRA1 risk genotype may play a role in determining neovascular subphenoptye, whereas genetics/demographics, smoking, and systemic health factors contribute to the development of advanced AMD in the presence of early AMD. RETINA 32:1950-1958, 2012