Park Hyo Jin, Kim Ju Hee, Yoon Jin Sook, Choi Yang Ji, Choi Yoon Hee, Kook Koung Hoon, Choi Ji Ha
Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Korea.
Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, Korea.
Yonsei Med J. 2017 Nov;58(6):1160-1169. doi: 10.3349/ymj.2017.58.6.1160.
This study was conducted to identify and to functionally characterize genetic variants in ST3GAL5 and ST8SIA1 in Korean patients with thyroid-associated ophthalmopathy (TAO).
Genetic analyses were conducted using DNA samples from TAO patients (n=50) and healthy subjects (n=48) to identify TAO-specific genetic variants of ST3GAL5 or ST8SIA1. The effect of each genetic variant on the transcription or expression of these genes was examined. Additionally, correlations between functional haplotypes of ST3GAL5 or ST8SIA1 and clinical characteristics of the patients were investigated.
Six promoter variants and one nonsynonymous variant of ST3GAL5 were identified, and four major promoter haplotypes were assembled. Additionally, three promoter variants and two major haplotypes of ST8SIA1 were identified. All ST3GAL5 and ST8SIA1 variants identified in TAO patients were also found in healthy controls. Promoter activity was significantly decreased in three promoter haplotypes of ST3GAL5 and increased in one promoter haplotype of ST8SIA1. Transcription factors activating protein-1, NKX3.1, and specificity protein 1 were revealed as having roles in transcriptional regulation of these haplotypes. The nonsynonymous variant of ST3GAL5, H104R, did not alter the expression of ST3GAL5. While no differences in clinical characteristics were detected in patients possessing the functional promoter haplotypes of ST3GAL5, exophthalmic values were significantly lower in patients with the ST8SIA1 haplotype, which showed a significant increase in promoter activity.
These results from genotype-phenotype analysis might suggest a possible link between the ST8SIA1 functional promoter haplotype and the clinical severity of TAO. However, further studies with larger sample sizes are warranted.
本研究旨在鉴定韩国甲状腺相关性眼病（TAO）患者中ST3GAL5和ST8SIA1基因的变异，并对其进行功能特征分析。
使用TAO患者（n = 50）和健康受试者（n = 48）的DNA样本进行基因分析，以鉴定ST3GAL5或ST8SIA1的TAO特异性基因变异。检测每个基因变异对这些基因转录或表达的影响。此外，研究了ST3GAL5或ST8SIA1功能单倍型与患者临床特征之间的相关性。
鉴定出ST3GAL5的六个启动子变异和一个非同义变异，并组装了四种主要的启动子单倍型。此外，鉴定出ST8SIA1的三个启动子变异和两种主要单倍型。在TAO患者中鉴定出的所有ST3GAL5和ST8SIA1变异也在健康对照中发现。ST3GAL5的三种启动子单倍型的启动子活性显著降低，而ST8SIA1的一种启动子单倍型的启动子活性增加。激活蛋白-1、NKX3.1和特异性蛋白1等转录因子在这些单倍型的转录调控中发挥作用。ST3GAL5的非同义变异H104R未改变ST3GAL5的表达。虽然具有ST3GAL5功能启动子单倍型的患者在临床特征上未检测到差异，但具有启动子活性显著增加的ST8SIA1单倍型的患者的眼球突出值显著较低。
这些基因分型-表型分析结果可能提示ST8SIA1功能启动子单倍型与TAO临床严重程度之间可能存在联系。然而，需要进一步进行更大样本量的研究。
