Human Glucocorticoid Receptor α Gene (NR3C1) Pharmacogenomics: Gene Resequencing and Functional Genomics
Human Glucocorticoid Receptor α Gene (NR3C1) Pharmacogenomics: Gene Resequencing and Functional Genomics
复制标题
DOI：
10.1210/jc.2008-2109
复制
发表时间：
2009-08-01
影响因子：
5.8
通讯作者：
Wang, Liewei
中科院分区：
文献类型：
--
作者：
Niu, Nifang;Manickam, Venkatraman;Wang, Liewei
内容：人糖皮质激素受体α（GR α）是调节多种生理和病理生理过程的核激素受体。对糖皮质激素的生理和治疗反应存在很大差异。多个先前的研究表明，在GR α（NR 3C 1）的遗传多态性可能发挥重要作用目的：本研究的目的是确定和确定常见的遗传变异在NR 3C 1的功能的影响。设计：我们重新测序NR 3C 1基因使用240个DNA样本从四个种族，其次是功能的特点，选择的多态性的影响。结果：在GR α中共鉴定出108个多态性，包括9个非同义编码单核苷酸多态性（cSNPs）和4个次要等位基因频率大于5%的同义cSNPs。功能研究表明，与野生型相比，编码Phe（65）瓦尔和Asp（687）Glu的SNPs显示蛋白质水平略微增加，并且Asp（687）Glu也引起GR α受体数量增加。此外，Ala（229）Thr和Ile（292）瓦尔在COS-1细胞中显示出轻微降低的配体结合亲和力。240个淋巴母细胞系中NR 3C 1基因表达的基因型-表型关联研究确定了位于非编码外显子1C 5 '上游的一个SNP Cm 746 T>C和位于该基因外显子1C的一个单倍型Cm 237 delC/Cm 238 C>T/Cm 240 G>C与GR α mRNA表达和GR α数量趋势相关。这些结果代表了理解GR α基因（NR 3C 1）中常见序列变异的功能作用以及这些SNP在翻译研究中的潜在应用的一步。（临床内分泌代谢杂志94：3072-3084，2009）
Context: The human glucocorticoid receptor alpha(GR alpha) is a nuclear hormone receptor that regulates multiple physiological and pathophysiological processes. There are large variations in both physiological and therapeutic response to glucocorticoids. Multiple previous studies suggested that genetic polymorphisms in GR alpha(NR3C1) might play an important role.Objective: The aim of the study was to identify and determine the functional implications of common genetic variation in NR3C1.Design: We resequenced the NR3C1 gene using 240 DNA samples from four ethnic groups, followed by functional characterization of the effects of selected polymorphisms.Results: A total of 108 polymorphisms were identified in GR alpha, including nine nonsynonymous coding single nucleotide polymorphisms (cSNPs) and four synonymous cSNPs with a minor allele frequency greater than 5%. Functional studies showed that SNPs encoding Phe(65) Val and Asp(687) Glu displayed slightly increased levels of protein compared with WT, and Asp(687) Glu also caused increased GR alpha receptor number. In addition, Ala(229) Thr and Ile(292) Val showed slightly decreased ligand binding affinity in COS-1 cells. A genotype-phenotype association study of NR3C1 gene expression in 240 lymphoblastoid cell lines identified one SNP, Cm746T>C, located 5'-upstream of noncoding exon 1C, and one haplotype, Cm237delC/Cm238C>T/Cm240G>C in exon 1C of the gene that were associated with GR alpha mRNA expression and a trend with GR alpha number.Conclusions: These results represent a step toward understanding the functional role of common sequence variation in the GR alpha gene (NR3C1) and the potential application of those SNPs in translational studies. (J Clin Endocrinol Metab 94: 3072-3084, 2009)