Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
JAMA Ophthalmol. 2018 Jun 1;136(6):682-688. doi: 10.1001/jamaophthalmol.2018.1231.
Previous studies investigating the association of single-nucleotide polymorphisms (SNPs) that confer increased risk of age-related macular degeneration (AMD) with pseudodrusen have yielded conflicting results and have not evaluated other AMD SNPs or pseudodrusen subtypes.
To determine the association of SNPs in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), HtrA serine peptidase 1 (HTRA1), complement C2 (C2), complement C3 (C3), lipase C (LIPC), and complement factor B (CFB) genes with the presence of pseudodrusen and pseudodrusen subtypes (ie, dot, reticular, and confluent).
DESIGN, SETTING, AND PARTICIPANTS: In this post hoc analysis of cross-sectional data from US participants in the Comparison of AMD Treatments Trials, genotyping was performed in 835 participants with TaqMan assays for the SNPs rs1061170 (Y402H variant in CFH), rs800292 (I62V variant in CFH), rs10490924 (A69S variant in ARMS2), rs11200638 (HTRA1), rs547154 (C2), rs2230199 (R102G variant in C3), rs10468017 (LIPC), and rs4151667 (L9H variant in CFB).
Presence and subtype of baseline pseudodrusen in either eye determined using color fundus photography, red-free images, and fluorescein angiograms.
Among 835 participants enrolled for genotyping, 755 (90.4%) were evaluated for pseudodrusen. Of these, 471 (62.4%) were female and 750 (99.3%) were white, and the mean (SD) age was 78.3 (7.5) years. A total of 213 of 755 participants (28.2%) had pseudodrusen (107 [14.2%] had dot pseudodrusen, 180 [23.8%] had reticular pseudodrusen, and 102 [13.5%] had confluent pseudodrusen). After adjusting for age, sex, and smoking status, the ARMS2 risk allele T was associated with higher risk of pseudodrusen (odds ratio [OR], 1.93; 95% CI, 1.19-3.12) for TT vs GG (P = .04). A similar association was found for HTRA1 (OR, 2.04; 95% CI, 1.26-3.31) for AA vs GG (P = .03). The CFH Y402H risk allele C was associated with lower risk of pseudodrusen (OR, 0.61; 95% CI, 0.38-0.97) for CC vs TT but was not statistically significant after correcting for multiple comparison (P = .20). CFH Y402H, ARMS2, HTRA1, and C3 were significantly associated with reticular pseudodrusen.
Among patients with neovascular AMD, the AMD risk alleles ARMS2 and HTRA1 were associated with an increased risk of pseudodrusen and the risk allele CFH Y402H was associated with lower risk of pseudodrusen, supporting findings from previous studies. Understanding the role of these SNPs in the development of pseudodrusen might improve our understanding of the pathogenesis of AMD and help develop future therapies.
先前研究调查了与年龄相关性黄斑变性（AMD）相关的单核苷酸多态性（SNP）与假性小体的关联，结果相互矛盾，并且尚未评估其他 AMD SNP 或假性小体亚型。
确定补体因子 H（CFH）、年龄相关性黄斑病变易感性 2（ARMS2）、HtrA 丝氨酸肽酶 1（HTRA1）、补体 C2（C2）、补体 C3（C3）、脂肪酶 C（LIPC）和补体因子 B（CFB）基因中的 SNP 与假性小体及其亚型（即点状、网状和融合性）的存在之间的关联。
设计、地点和参与者：这是美国比较 AMD 治疗试验中横断面数据的事后分析，使用 TaqMan 分析对 835 名参与者进行了基因分型，用于 SNP rs1061170（CFH 的 Y402H 变体）、rs800292（CFH 的 I62V 变体）、rs10490924（ARMS2 的 A69S 变体）、rs11200638（HTRA1）、rs547154（C2）、rs2230199（C3 的 R102G 变体）、rs10468017（LIPC）和 rs4151667（CFB 的 L9H 变体）的 SNP 进行基因分型。
使用眼底彩色摄影、无赤光图像和荧光素血管造影确定基线假性小体的存在和亚型。
在 835 名入组进行基因分型的参与者中，755 名（90.4%）进行了假性小体评估。其中，471 名（62.4%）为女性，750 名（99.3%）为白人，平均（标准差）年龄为 78.3（7.5）岁。共有 755 名参与者中的 213 名（28.2%）患有假性小体（107 名[14.2%]患有点状假性小体，180 名[23.8%]患有网状假性小体，102 名[13.5%]患有融合性假性小体）。在调整年龄、性别和吸烟状况后，ARMS2 风险等位基因 T 与假性小体风险增加相关（优势比[OR]，1.93；95%CI，1.19-3.12），TT 比 GG（P=0.04）。类似的关联也在 HTRA1 中发现（OR，2.04；95%CI，1.26-3.31），AA 比 GG（P=0.03）。CFH Y402H 风险等位基因 C 与假性小体风险降低相关（OR，0.61；95%CI，0.38-0.97），CC 比 TT，但在进行多次比较校正后没有统计学意义（P=0.20）。CFH Y402H、ARMS2、HTRA1 和 C3 与网状假性小体显著相关。
在患有新生血管性 AMD 的患者中，AMD 风险等位基因 ARMS2 和 HTRA1 与假性小体风险增加相关，CFH Y402H 风险等位基因与假性小体风险降低相关，这支持了先前研究的结果。了解这些 SNP 在假性小体发展中的作用可能有助于我们更好地理解 AMD 的发病机制，并有助于开发未来的治疗方法。
