Prospective study of common variants in the retinoic acid receptor-related orphan receptor α gene and risk of neovascular age-related macular degeneration

Abstract

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.

Figure 1

Linkage Disequilibrium (D’) between the 18 SNPs genotyped in the RORalpha gene in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. LD was determined using the program Haploview and LD blocks were defined using the Gabriel Rule. Boxes are shaded increasingly darker to represent higher percentage of LD and the numbers listed in each square represent the D’ (Part 1a) and r2 values (Part 1b). A completely shaded in box represents complete LD. Three haplotype blocks were generated for this cohort of NHS and HPFS participants.

Figure 1

Linkage Disequilibrium (D’) between the 18 SNPs genotyped in the RORalpha gene in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. LD was determined using the program Haploview and LD blocks were defined using the Gabriel Rule. Boxes are shaded increasingly darker to represent higher percentage of LD and the numbers listed in each square represent the D’ (Part 1a) and r2 values (Part 1b). A completely shaded in box represents complete LD. Three haplotype blocks were generated for this cohort of NHS and HPFS participants.