HTRA1 variants in exudative age-related macular degeneration and interactions with smoking and CFH
HTRA1 variants in exudative age-related macular degeneration and interactions with smoking and CFH
复制标题
DOI：
10.1167/iovs.07-1520
复制
发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Pang, Chi Pui
中科院分区：
文献类型：
--
作者：
Tam, Pancy O. S.;Ng, Tsz Kin;Pang, Chi Pui
目的。直到最近的全基因组关联研究显示，CFH中的Tyr402His和HTRA1中的rs11200638是与AMD相关的遗传变异，年龄相关性黄斑变性（AMD）的基因定位才成功。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患者和183例性别和年龄匹配的对照组进行了HTRA1启动子、剪接区和编码外显子的测序。还记录了CFH基因型和吸烟状况。在HTRA1的启动子和第一个外显子中发现了4个显著snp: rs11200638 （-625G>A）、rs2672598 （-487T>C）、rs1049331 （102C>T, Ala34Ala）和rs2293870 (108G>T, Gly36Gly)， 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是最显著的相关SNP，优势比（OR）为7.6 （95% CI: 3.94 ~ 14.51）。跨启动子和外显子1 ACCTT的一个风险单倍型块显着易患AMD （P = 6.68 × 10(-14)）。在两个模型中，吸烟和CFH的rs800292 （184G>A, Val62Ile）存在显著的独立加性效应。吸烟和rs11200638 （HTRA1）联合导致风险增加15.7倍，而rs800292和rs11200638联合导致风险增加23.3倍。人群归因风险（PAR）极高，为78%。CFH和HTRA1的加性作用对渗出性AMD的发展有很大的影响。本研究发现的htra1 -吸烟累加效应进一步提示了这一环境风险因素在AMD中的重要性。
PURPOSE. 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.METHODS. 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.RESULTS. 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.CONCLUSIONS. 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.