MMP20 and ARMS2/HTRA1 Are Associated with Neovascular Lesion Size in Age-Related Macular Degeneration
MMP20 and ARMS2/HTRA1 Are Associated with Neovascular Lesion Size in Age-Related Macular Degeneration
复制标题
DOI：
10.1016/j.ophtha.2015.07.032
复制
发表时间：
2015-11-01
期刊：
影响因子：
13.7
通讯作者：
Yoshimura, Nagahisa
中科院分区：
文献类型：
--
作者：
Akagi-Kurashige, Yumiko;Yamashiro, Kenji;Yoshimura, Nagahisa
目的：视网膜相关性黄斑变性（AMD）是导致严重视力损害的主要原因。尽管治疗，中心暗点往往仍然存在。暗点的大小取决于脉络膜新生血管膜的病变大小，并显著影响患者的生活质量，并且新生血管的病变大小也影响对治疗的反应。本研究的目的是确定与新生血管性AMD中新生血管病变大小相关的基因。设计：全基因组关联研究（GWAS）。参与者：我们纳入了1146例日本新生血管性AMD患者。方法：我们对1146例患者中的AMD病变大小进行了2阶段GWAS，作为一个数量性状。（第一阶段：727，第二阶段：419）日本新生血管性AMD患者。治疗前用荧光素血管造影测量病灶的最大线性尺寸。我们研究了每个单核苷酸多态性（SNP）的基因型分布和性状之间的关联，使用加性模型调整年龄和性别。为了评估AMD发展和与病变大小相关的SNP之间的关联，我们还进行了一项病例对照研究，使用来自这1146名日本患者的基因型数据作为病例受试者，使用来自Nagahama研究的固定数据集作为对照受试者。主要结果测量：与新生血管性AMD病变大小相关的基因。在发现阶段，MMP 20的rs 10895322显示出全基因组显著性P值为6.95x10（-8），ARMS 2/HTRA 1的rs 2284665显示出P值为1.55x10（-7）。这两个SNP的关联在复制阶段被成功复制，并且两个阶段的荟萃分析显示全基因组显著P值（分别为2.80x10（-9）和4.41x10（-9））。在使用3248名日本受试者作为对照的病例对照研究中，我们没有发现MMP 20 rs 10895322对AMD发展的贡献。虽然MMP 20一直被认为是只在牙齿组织中表达，我们证实MMP 20的表达在人视网膜和视网膜色素上皮/脉络膜polymerase chain reaction.Conclusions：脉络膜新生血管的生长在AMD的影响2个基因：MMP 20，一个新证实的基因在视网膜中表达，和ARMS 2/HTRA 1，一个众所周知的AMD易感基因。(C)2015年，美国眼科学会。
Purpose: Age-related macular degeneration (AMD) is the leading cause of severe visual impairment. Despite treatment, a central scotoma often remains. The size of the scotoma depends on the lesion size of the choroidal neovascular membrane and significantly affects the patient's quality of life, and the lesion size of neovascularization also affects response to treatments. The aim of this study was to identify genes associated with the neovascular lesion size in neovascular AMD.Design: A genome-wide association study (GWAS).Participants: We included 1146 Japanese patients with neovascular AMD.Methods: We performed a 2-stage GWAS for the lesion size of AMD as a quantitative trait among 1146 (first stage: 727, second stage: 419) Japanese patients with neovascular AMD. Lesion size was determined by the greatest linear dimension measured with fluorescein angiography examination before treatment. We examined the association between the genotypic distribution of each single nucleotide polymorphism (SNP) and the trait using an additive model adjusted for age and sex. To evaluate the associations between AMD development and SNPs associated with lesion size, we also performed a case-control study by using the genotype data from these 1146 Japanese patients as case subjects and the fixed dataset from the Nagahama Study as control subjects.Main Outcome Measures: Genes associated with the lesion size in neovascular AMD.Results: In the discovery stage, rs10895322 in MMP20 showed a genome-wide significant P value of 6.95x10(-8), and rs2284665 in ARMS2/HTRA1 showed a P value of 1.55x10(-7). The associations of these 2 SNPs were successfully replicated in the replication stage, and a meta-analysis of both stages showed genome-wide significant P values (2.80x10(-9) and 4.41x10(-9), respectively). In a case-control study using 3248 Japanese subjects as controls, we could not find contribution of MMP20 rs10895322 for AMD development. Although MMP20 has been thought to be expressed only in dental tissues, we confirmed MMP20 expression in the human retina and retinal pigment epithelium/choroid with polymerase chain reaction.Conclusions: The growth of choroidal neovascularization in AMD would be affected by 2 genes: MMP20, a newly confirmed gene expressed in the retina, and ARMS2/HTRA1, a well-known susceptibility gene for AMD. (C) 2015 by the American Academy of Ophthalmology.