Fingert John H, Alward Wallace L, Wang Kai, Yorio Thomas, Clark Abbot F
Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USA.
Mol Vis. 2010 Apr 3;16:596-601.
While chronic glucocorticoid (GC) therapy leads to ocular hypertension in about one third of individuals, almost all primary open-angle glaucoma (POAG) patients show this response and are called "steroid responders." Two differentially spliced isoforms of the glucocorticoid receptor (GR), GRalpha and GRbeta, regulate GC responsiveness in trabecular meshwork (TM) cells. GRbeta acts as a dominant negative regulator of GC activity and is expressed at lower levels in glaucomatous TM cells, making them more sensitive to GCs. Several arginine/serine-rich splicing factor (SR) proteins have been implicated in alternative splicing of the GR. We have previously demonstrated that immunophilins FKBP5 and FKBP4 are required for GRalpha and GRbeta translocation into the nucleus, which is essential for their biologic activity. The purpose of the present study was to use single nucleotide polymorphism (SNP) genotyping to determine whether there are any allele frequency differences in GR, FKBP4/5, or SR genes between normal control, POAG, and steroid responder populations.
Clinically characterized individuals (400 normal controls, 197 POAG, and 107 steroid responders) were recruited from the U. Iowa Ophthalmology Clinics after IRB approved consent. Genotyping of DNA samples for 48 SNPs in SFRS3, SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 was done at GeneSeek using a mass spectroscopy based system.
All 48 SNPs displayed high call rates (99%). There were no significant differences in allele frequencies or genotypes in SNPs for SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 between the 3 groups. Up to three SNPs in SFRS3 had p-values <0.05 when comparing controls to POAG or steroid responders, but this statistical significance was lost when the p values were adjusted for multiple measures.
Although these 6 genes may be involved in the pathogenesis of GC-induced ocular hypertension, it does not appear that major heritable risk alleles in these genes are responsible for the development of GC-induced ocular hypertension or POAG.
虽然慢性糖皮质激素（GC）治疗会使约三分之一的个体出现眼压升高，但几乎所有原发性开角型青光眼（POAG）患者都会出现这种反应，这些患者被称为“类固醇反应者”。糖皮质激素受体（GR）有两种差异剪接的异构体，即GRα和GRβ，它们调节小梁网（TM）细胞对GC的反应性。GRβ作为GC活性的显性负调节因子，在青光眼性TM细胞中的表达水平较低，使其对GC更敏感。几种富含精氨酸/丝氨酸的剪接因子（SR）蛋白与GR的可变剪接有关。我们之前已经证明，免疫亲和蛋白FKBP5和FKBP4是GRα和GRβ转运到细胞核所必需的，而这对它们的生物学活性至关重要。本研究的目的是使用单核苷酸多态性（SNP）基因分型来确定正常对照、POAG和类固醇反应者群体之间GR、FKBP4/5或SR基因的等位基因频率是否存在差异。
在获得机构审查委员会（IRB）批准的同意后，从爱荷华大学眼科诊所招募了具有临床特征的个体（400名正常对照、197名POAG患者和107名类固醇反应者）。使用基于质谱的系统在GeneSeek对SFRS3、SFRS5、SFRS9、FKBP4、FKBP5和NR3C1中的48个SNP进行DNA样本基因分型。
所有48个SNP的检出率都很高（99%）。在三组之间，SFRS5、SFRS9、FKBP4、FKBP5和NR3C1的SNP等位基因频率或基因型没有显著差异。在将对照组与POAG或类固醇反应者进行比较时，SFRS3中多达三个SNP的p值<0.05，但在对多个测量值进行p值调整后，这种统计学显著性消失了。
虽然这6个基因可能参与GC诱导的眼压升高的发病机制，但这些基因中的主要遗传风险等位基因似乎并不导致GC诱导的眼压升高或POAG的发生。
