Schaumberg Debra A, Chasman Daniel, Morrison Margaux A, Adams Scott M, Guo Qun, Hunter David J, Hankinson Susan E, DeAngelis Margaret M
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA.
Arch Ophthalmol. 2010 Nov;128(11):1462-71. doi: 10.1001/archophthalmol.2010.261.
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.
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.
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.
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.
通过先前的微阵列表达研究、连锁数据、生物学合理性以及两项基于临床的横断面研究，维甲酸受体（RAR）相关孤儿受体α基因（RORA）被认为是年龄相关性黄斑变性（AMD）的候选基因。我们旨在确定RORA基因的常见变异是否能预测新生血管性AMD的未来风险。
在护士健康研究和卫生专业人员随访研究中的一项前瞻性巢式病例对照研究中，我们对164例发生新生血管性AMD的病例和485例年龄及性别匹配的对照者进行了RORA基因第1内含子中18个变异的基因分型。我们确定了每个变异的新生血管性AMD发病率比及95%置信区间（CI），并研究了与其他AMD相关变异及可改变风险因素的相互作用。
我们鉴定出一个单核苷酸多态性（rs12900948）与新生血管性AMD发病率增加显著相关。携带1个和2个G等位基因拷贝的参与者发生新生血管性AMD的可能性分别是1.73倍（CI，1.32 - 2.27）和2.99倍（CI，1.74 - 5.14）。rs12900948的G等位基因和ARMS2 A69S均为纯合子的个体发生新生血管性AMD的风险增加40.8倍（CI，10.1 - 164；P = 0.017）。携带2个G等位基因拷贝的吸烟者发生新生血管性AMD的风险为9.89倍，但相互作用不显著（P = 0.08）。我们鉴定出一个与AMD相关的显著单倍型块，包含单核苷酸多态性rs730754、rs8034864和rs12900948，与所有其他单倍型相比，ACA的P值为1.16×10⁻⁹，ACG的P值为5.85×10⁻¹²，GAA的P值为0.0001。
RORA基因内的常见变异和单倍型似乎与ARMS2 A69S多态性协同作用，增加新生血管性AMD的风险。这些数据进一步证明了将遗传和可改变风险因素与AMD发生联系起来的高度复杂性，并应有助于风险预测工作。
