Tam Pancy O S, Ng Tsz Kin, Liu David T L, Chan Wai Man, Chiang Sylvia W Y, Chen Li Jia, DeWan Andrew, Hoh Josephine, Lam Dennis S C, Pang Chi Pui
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2357-65. doi: 10.1167/iovs.07-1520. Epub 2008 Mar 3.
Mapping the genes for age-related macular degeneration (AMD) had not been successful until recent genome-wide association studies revealed Tyr402His in CFH and rs11200638 in HTRA1 as AMD-related genetic variants. This study was conducted to identify other critical factors in HTRA1 that are associated with exudative AMD.
The promoter, splice regions, and coding exons of HTRA1 were sequenced in 163 patients with exudative AMD and 183 sex- and age-matched control subjects. Also documented were the CFH genotype and smoking status.
Four significant SNPs were found in the promoter and the first exon of HTRA1: rs11200638 (-625G>A), rs2672598 (-487T>C), rs1049331 (102C>T, Ala34Ala), and rs2293870 (108G>T, Gly36Gly) with respective P = 1.7 x 10(-14), 3.0 x 10(-10), 3.7 x 10(-12), and 3.7 x 10(-12). Among them, rs11200638 is the most significant associated SNP with a high odds ratio (OR) of 7.6 (95% CI: 3.94-14.51). One risk haplotype block across the promoter and exon 1, ACCTT, significantly predisposes to AMD (P = 6.68 x 10(-14)). In both models, significant independent additive effects were identified with smoking and rs800292 (184G>A, Val62Ile) of CFH. Smoking and rs11200638 (HTRA1) combined caused a 15.7-fold increased risk, whereas combined rs800292 and rs11200638 caused a 23.3-fold increased risk. An extremely high population attributable risk (PAR) of 78% was also found.
A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD.
在近期全基因组关联研究揭示CFH基因中的Tyr402His以及HTRA1基因中的rs11200638为年龄相关性黄斑变性（AMD）相关遗传变异之前，绘制AMD相关基因的工作一直未取得成功。本研究旨在确定HTRA1中与渗出性AMD相关的其他关键因素。
对163例渗出性AMD患者及183例年龄和性别匹配的对照者的HTRA1启动子、剪接区域及编码外显子进行测序。同时记录CFH基因型和吸烟状况。
在HTRA1启动子和第一个外显子中发现4个显著的单核苷酸多态性（SNP）：rs11200638（-625G>A）、rs2672598（-487T>C）、rs1049331（102C>T，丙氨酸34丙氨酸）和rs2293870（108G>T，甘氨酸36甘氨酸），其P值分别为1.7×10⁻¹⁴、3.0×10⁻¹⁰、3.7×10⁻¹²和3.7×10⁻¹²。其中，rs11200638是最显著相关的SNP，优势比（OR）高达7.6（95%可信区间：3.94 - 14.51）。一个跨越启动子和外显子1的风险单倍型块ACCTT显著增加AMD易感性（P = 6.68×10⁻¹⁴）。在两个模型中，均确定吸烟和CFH的rs800292（184G>A，缬氨酸62异亮氨酸）具有显著的独立累加效应。吸烟与rs11200638（HTRA1）共同作用使风险增加15.7倍，而rs800292与rs11200638共同作用使风险增加23.3倍。还发现极高的人群归因风险（PAR）为78%。
显示了CFH和HTRA1的累加效应在渗出性AMD发生发展中的高度影响。本研究中发现的HTRA1 - 吸烟累加效应进一步表明该环境风险因素在AMD中的重要性。
