A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1.
A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1.
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DOI：
10.1371/journal.pgen.1000660
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发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Matsuda F
中科院分区：
文献类型：
--
作者：
Nakanishi H;Yamada R;Gotoh N;Hayashi H;Yamashiro K;Shimada N;Ohno-Matsui K;Mochizuki M;Saito M;Iida T;Matsuo K;Tajima K;Yoshimura N;Matsuda F
近视是世界范围内最常见的眼部疾病之一。病理性近视，也称为高度近视，占总人口的1%至5%，是发达国家法律的失明的主要原因之一。为了确定与日本人病理性近视相关的遗传决定因素，我们进行了一项全基因组关联研究，在两阶段设计中分析了830例病例和1，911名普通人群对照的411，777个SNP（第一阶段为297例病例和934名对照，第二阶段为533例病例和977名对照）。我们选择了22个在第一阶段显示P值小于10 - 4的SNP，并在第二阶段测试它们的关联性。结合第一阶段和第二阶段的荟萃分析确定了染色体11q24.1处的SNP rs 577948，该SNP与疾病相关（P = 2.22×10−7，OR为1.37，95%置信区间：1.21-1.54）。 在包含rs 577948的200-kb DNA内鉴定了两个基因，BLID和LOC 399959。RT-PCR分析表明，这两个基因在人视网膜组织中表达。我们的研究结果有力地表明，在11q24.1区域是一个新的易感基因位点的病理性近视在日本。近视是一种常见的眼轴延长性眼病。病理性近视或高度近视是近视的一个子集，其特征在于眼睛的过度轴向伸长和退行性改变，是视力损害的主要原因。由于遗传因素在其发展中起着重要作用，因此确定遗传决定因素是一个紧迫而重要的问题。虽然基于家族的连锁分析已经分离出至少16个病理性或普通近视的易感染色体位点，但尚未鉴定出与该疾病相关的基因。我们进行了第一个病理性近视的全基因组病例/对照关联研究，采用两阶段设计，使用了411，777个标记物，其中包括830名日本患者和1，911名日本对照。我们在染色体11q24.1上发现了一个强烈提示疾病易感性的区域，该区域含有BLID和LOC 399959。RT-PCR证实它们在人视网膜中有表达。BLID编码凋亡性细胞死亡的诱导物，并且已知凋亡在病理性近视中起重要的功能作用。我们相信，我们的研究有助于进一步剖析病理性近视的发展和进展的分子事件。
Myopia is one of the most common ocular disorders worldwide. Pathological myopia, also called high myopia, comprises 1% to 5% of the general population and is one of the leading causes of legal blindness in developed countries. To identify genetic determinants associated with pathological myopia in Japanese, we conducted a genome-wide association study, analyzing 411,777 SNPs with 830 cases and 1,911 general population controls in a two-stage design (297 cases and 934 controls in the first stage and 533 cases and 977 controls in the second stage). We selected 22 SNPs that showed P-values smaller than 10−4 in the first stage and tested them for association in the second stage. The meta-analysis combining the first and second stages identified an SNP, rs577948, at chromosome 11q24.1, which was associated with the disease (P = 2.22×10−7 and OR of 1.37 with 95% confidence interval: 1.21–1.54). Two genes, BLID and LOC399959, were identified within a 200-kb DNA encompassing rs577948. RT–PCR analysis demonstrated that both genes were expressed in human retinal tissue. Our results strongly suggest that the region at 11q24.1 is a novel susceptibility locus for pathological myopia in Japanese. Myopia is one of the most common ocular disorders with elongation of axis of the eyeball. Pathological myopia or high myopia, a subset of myopia which is characterized with excessive axial elongation and degenerative changes of the eye, is a leading cause of visual impairment. Since genetic factors play significant roles in its development, identification of genetic determinants is an urgent and important issue. Although family-based linkage analyses have isolated at least 16 susceptible chromosomal loci for pathological or common myopia, no gene responsible for the disease has been identified. We conducted the first genome-wide case/control association study of pathological myopia in a two-stage design using 411,777 markers with 830 Japanese patients and 1,911 Japanese controls. We identified a region strongly suggestive for the disease susceptibility at chromosome 11q24.1 containing BLID and LOC399959. Their expression was confirmed in human retina with RT–PCR. BLID encodes an inducer of apoptotic cell death, and apoptosis is known to play an important functional role in pathological myopia. We believe that our study contributes to further dissect the molecular events underlying the development and progression of pathological myopia.
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