Francis Peter J, Zhang Hong, Dewan Andrew, Hoh Josephine, Klein Michael L
Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.
Mol Vis. 2008 Aug 4;14:1395-400.
To estimate the joint effects of single nucleotide polymorphisms (SNPs) in the genes complement factor H (CFH), HtrA serine peptidase 1 (HTRA1), and age-related maculopathy susceptibility 2 (LOC387715/ARMS2) in a Caucasian age related macular degeneration (AMD) case-control cohort.
We genotyped three SNPs, rs1061170 (exon 9, CFH), rs11200638 (HTRA1 promoter, -512 bp), and rs10490924 (6.6 kb upstream of HTRA1 in LOC387715/ARMS2) in 333 cases with advanced AMD (choroidal neovascularization [CNV] and geographic atrophy) and 171 age-matched examined controls. Association tests were performed for individual SNPs and jointly with the CFH SNP Y402H. Analyses for interaction were also performed.
The linkage disequilibrium measure for two SNPs on 10q26, rs10490924 and rs11200638, is D'=0.8 and all four possible haplotypes of the two SNPs were detected in the samples. The allelic association test for rs11200638 on the promoter of HTRA1 yielded p-values less than 10(-10) for geographic atrophy, less than 10(-16) for neovascularization, and less than 10(-19) for the pooled phenotypes (with an odds ration [OR] of 3.973; 95% confidence interval [CI] 2.928, 5.390). Disease risk is conferred in a dosage-dependent fashion. Similar figures were observed for the LOC387715/ARMS2 SNP. No interaction was detected between either between the 10q26 SNPs or the CFH SNP.
This is the first analysis to show that the two 10q26 SNPs are not in complete linkage disequilibrium. Our studies however show that both the HTRA1 and LOC387715/ARMS2 SNP appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH.
在一个白种人年龄相关性黄斑变性（AMD）病例对照队列中，评估补体因子H（CFH）、HtrA丝氨酸蛋白酶1（HTRA1）和年龄相关性黄斑病变易感性2（LOC387715/ARMS2）基因中的单核苷酸多态性（SNP）的联合效应。
我们对333例晚期AMD（脉络膜新生血管[CNV]和地图样萎缩）患者和171例年龄匹配的对照进行了三个SNP的基因分型，即rs1061170（CFH第9外显子）、rs11200638（HTRA1启动子，-512 bp）和rs10490924（LOC387715/ARMS2中HTRA1上游6.6 kb处）。对单个SNP以及与CFH SNP Y402H联合进行关联测试。还进行了相互作用分析。
10q26上两个SNP，rs10490924和rs11200638的连锁不平衡度量D'=0.8，并且在样本中检测到了这两个SNP的所有四种可能单倍型。HTRA1启动子上rs11200638的等位基因关联测试显示，对于地图样萎缩，p值小于10^(-10)；对于新生血管形成，p值小于10^(-16)；对于合并表型，p值小于10^(-19)（优势比[OR]为3.973；95%置信区间[CI]为2.928, 5.390）。疾病风险以剂量依赖方式赋予。对于LOC387715/ARMS2 SNP也观察到类似数据。在10q26 SNPs之间或CFH SNP之间均未检测到相互作用。
这是首次分析表明10q26上的两个SNP并非完全连锁不平衡。然而，我们的研究表明，HTRA1和LOC387715/ARMS2 SNP似乎对疾病风险（地图样萎缩和脉络膜新生血管形成）的贡献相同，且没有与CFH相互作用的证据。
