Replication of the TCF4 Intronic Variant in Late-Onset Fuchs Corneal Dystrophy and Evidence of Independence from the FCD2 Locus
Replication of the TCF4 Intronic Variant in Late-Onset Fuchs Corneal Dystrophy and Evidence of Independence from the FCD2 Locus
复制标题
DOI：
10.1167/iovs.10-6497
复制
发表时间：
2011-04-01
影响因子：
4.4
通讯作者：
Gottsch, John D.
中科院分区：
文献类型：
--
作者：
Riazuddin, S. Amer;McGlumphy, Elyse J.;Gottsch, John D.
目的。Fuchs角膜营养不良是一种常染色体显性遗传性角膜内皮疾病，具有不同的外显率和表现率。最近，与晚发性FCD相关的TCF4基因内含子变异rs613872被报道。这项研究是为了在我们的FCD患者队列中检查这种相关性，评估这一发现的意义，并在被映射的FCD2基因座的背景下调查TCF4的候选。方法：作者招募了170名晚发性FCD患者和180名年龄匹配的对照。采集血样，提取基因组DNA。在这个队列和之前报道的三个FCD2连锁家系中，一个跨越整个TCF4基因座的九个SNPs组成的小组被进行了基因分型。结果：rs613872的风险等位基因G与晚发性FCD显著相关(优势比为4.2；P=4.28×10(-15))，并且存在于没有性别偏见的男性和女性患者中，重复了最近的发现，尽管作者发现与疾病的严重程度没有明显的相关性。此外，在三个FCD2连锁的家系中，风险等位基因与疾病表型中的任何一个都不存在协同分离。作者未在TCF4编码区发现任何致病变异。结论作者首次报道了rs613872的独立复制导致迟发性FCD的风险。他们的数据表明，这一风险因素可能独立于FCD2基因座，其因果关系尚不清楚。(投资眼科VS科学。2011年；52：2825-2829)doi：10.1167/iovs.10-6497
PURPOSE. Fuchs corneal dystrophy (FCD) is an autosomal dominant disease of the corneal endothelium with variable penetrance and expressivity. Recently, rs613872, an intronic variation of TCF4 associated with late-onset FCD, was reported. The present study was undertaken to examine this association in our cohort of FCD patients, to assess the significance of this finding, and to investigate the candidacy of TCF4 in the context of the mapped FCD2 locus.METHODS. The authors recruited 170 patients with late-onset FCD and 180 age-matched controls. Blood samples were collected, and genomic DNA was extracted. A panel of nine SNPs spanning the entire TCF4 locus was genotyped both on this cohort and on three previously reported FCD2-linked families. The association of an individual SNP with late-onset FCD was evaluated with the Fisher exact test, and the coding exons and exon-intron boundaries of TCF4 were sequenced in 96 affected persons.RESULTS. The risk allele G of rs613872 is associated significantly with late-onset FCD (odds ratio, 4.2; P = 4.28 x 10(-15)) and was present in male and female affected persons without any sex bias, replicating recent findings, though the authors found no apparent correlation with the severity of the disease phenotype. Moreover, the risk allele did not cosegregate with the disease phenotype in any of the three FCD2-linked families. The authors did not identify any pathogenic variants in the coding region of TCF4.CONCLUSIONS. The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown. (Invest Ophthalmol Vis Sci. 2011;52:2825-2829) DOI:10.1167/iovs.10-6497