Set-Based Joint Test of Interaction Between SNPs in the VEGF Pathway and Exogenous Estrogen Finds Association With Age-Related Macular Degeneration
Set-Based Joint Test of Interaction Between SNPs in the VEGF Pathway and Exogenous Estrogen Finds Association With Age-Related Macular Degeneration
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DOI：
10.1167/iovs.14-14494
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发表时间：
2014-08-01
影响因子：
4.4
通讯作者：
Scott, William K.
中科院分区：
文献类型：
--
作者：
Courtenay, Monique D.;Cade, William H.;Scott, William K.
目的.视网膜相关性黄斑变性（AMD）是发达国家不可逆视力丧失的主要原因。其病因包括遗传和环境因素。虽然VEGFA变异与AMD相关，但VEGF通路内变异的联合作用及其与非遗传因素的相互作用尚未研究。使用Affyestival6.0芯片组对1207例AMD患者和686例对照者的668，238个单核苷酸多态性（SNP）进行基因分型。通过问卷调查收集环境暴露情况。使用来自Kraft双自由度（2df）联合检验的每个SNP处的卡方（2）统计量进行基于集合的检验。基于途径和基因的检验统计量计算为所有独立SNP统计量的平均值。将表型标记排列10，000次以产生经验P值。虽然VEGF通路的主要作用尚未确定，但当考虑避孕药（BCP）使用时，该通路与女性中的新生血管性AMD相关（P = 0.017）。VEGF亚通路的分析显示，当考虑BCP使用时，增殖亚通路中的SNP与新生血管性AMD相关（P = 0.029）。还观察到该子途径内的名义上显著的基因。BCP使用分层揭示了服用BCP的女性中新的显著遗传效应。这些结果表明，一些AMD的遗传风险因素可能会被揭示，只有当复杂的风险因素之间的关系被认为是。这显示了探索先前相关基因的途径以发现新效应的效用。它还证明了在SNP、基因或途径水平上将环境暴露纳入遗传关联测试的重要性。
PURPOSE. Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in developed countries. Its etiology includes genetic and environmental factors. Although VEGFA variants are associated with AMD, the joint action of variants within the VEGF pathway and their interaction with nongenetic factors have not been investigated.METHODS. Affymetrix 6.0 chipsets were used to genotype 668,238 single nucleotide polymorphisms (SNPs) in 1207 AMD cases and 686 controls. Environmental exposures were collected by questionnaire. A set-based test was conducted using the chi(2) statistic at each SNP derived from Kraft's two degree of freedom (2df) joint test. Pathway- and gene-based test statistics were calculated as the mean of all independent SNP statistics. Phenotype labels were permuted 10,000 times to generate an empirical P value.RESULTS. While a main effect of the VEGF pathway was not identified, the pathway was associated with neovascular AMD in women when accounting for birth control pill (BCP) use (P = 0.017). Analysis of VEGF's subpathways showed that SNPs in the proliferation subpathway were associated with neovascular AMD (P = 0.029) when accounting for BCP use. Nominally significant genes within this subpathway were also observed. Stratification by BCP use revealed novel significant genetic effects in women who had taken BCPs.CONCLUSIONS. These results illustrate that some AMD genetic risk factors may be revealed only when complex relationships among risk factors are considered. This shows the utility of exploring pathways of previously associated genes to find novel effects. It also demonstrates the importance of incorporating environmental exposures in tests of genetic association at the SNP, gene, or pathway level.