A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in the ABCA4 Gene
A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in the ABCA4 Gene
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DOI：
10.1167/iovs.11-8785
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发表时间：
2012-04-01
影响因子：
4.4
通讯作者：
Weber, Bernhard H. F.
中科院分区：
文献类型：
--
作者：
Fritsche, Lars G.;Fleckenstein, Monika;Weber, Bernhard H. F.
目的。年龄相关性黄斑变性（AMD）是一种患病率高、病因复杂的异质性疾病，涉及遗传和环境因素。通过眼底自身荧光（FAF）成像，AMD可分为几种不同的表型，其中一个亚组的特征是细颗粒状，周围有点状斑点（GPS[+]）。GPS[+]的一些特征与Stargardt病（STGD1）重叠，STGD1是一种由atp结合盒转运体4 （ABCA4）基因双等位基因序列变异引起的隐性黄斑营养不良。本研究旨在探讨ABCA4在GPS中的作用[+]。对25例GPS[+]表型患者和29例无GPS （GPS[-]）症状的地理萎缩(GA)- amd患者进行了ABCA4基因测序。此外，还评估了三个已知AMD易感性位点的风险增加等位基因的频率，包括补体因子H （CFH）、年龄相关性黄斑病变易感性2 （ARMS2）和补体成分3 （C3）。我们证明GPS[+]与单等位ABCA4序列变异显著相关。此外，在GPS[+]和STGD1患者中，CFH、ARMS2和C3的AMD风险增加等位基因频率相似，这两个亚类的风险等位基因频率与NHLBI外显子组测序项目中3,510个个体的基于人群的对照个体相当。我们的数据表明，GPS[+]表型是由ABCA4的单等位基因变异引起的，而不太可能是由CFH、ARMS2和C3的成熟的AMD风险增加等位基因引起的。这些发现为ABCA4在一小部分AMD患者病因学中的复杂作用提供了支持。（Invest Ophthalmol Vis Sci. 2012;53:2112-2118） DOI:10.1167/iovs.11-8785
PURPOSE. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+].METHODS. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated.RESULTS. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project.CONCLUSIONS. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD. (Invest Ophthalmol Vis Sci. 2012;53:2112-2118) DOI:10.1167/iovs.11-8785