Objectives: The retinoic acid receptor (RAR)-related orphan receptor α gene (RORA) is implicated as a candidate for age-related macular degeneration (AMD) through a previous microarray expression study, linkage data, biological plausibility, and 2 clinic-based cross-sectional studies. We aimed to determine if common variants in RORA predict future risk of neovascular AMD.
Methods: We measured genotypes for 18 variants in intron 1 of the RORA gene among 164 cases who developed neovascular AMD and 485 age- and sex-matched controls in a prospective, nested, case-control study within the Nurses' Health Study and the Health Professionals Follow-up Study. We determined the incidence rate ratios and 95% confidence intervals (CI) for neovascular AMD for each variant and examined interactions with other AMD-associated variants and modifiable risk factors.
Results: We identified one single-nucleotide polymorphism (rs12900948) that was significantly associated with increased incidence of neovascular AMD. Participants with 1 and 2 copies of the G allele were 1.73 (CI, 1.32-2.27) and 2.99 (CI, 1.74-5.14) times more likely to develop neovascular AMD. Individuals homozygous for both the G allele of rs12900948 and ARMS2 A69S had a 40.8-fold increased risk of neovascular AMD (CI, 10.1-164; P = .017). Cigarette smokers who carried 2 copies of the G allele had a 9.89-fold risk of neovascular AMD but the interaction was not significant (P = .08). We identified a significant AMD-associated haplotype block containing the single-nucleotide polymorphisms rs730754, rs8034864, and rs12900948, with P values for ACA = 1.16 × 10(-9), ACG = 5.85 × 10(-12), and GAA = .0001 when compared with all other haplotypes.
Conclusions: Common variants and haplotypes within the RORA gene appear to act synergistically with the ARMS2 A69S polymorphism to increase risk of neovascular AMD. These data add further evidence of a high level of complexity linking genetic and modifiable risk factors to AMD development and should help efforts at risk prediction.