Zaorska Katarzyna, Zawierucha Piotr, Ostalska-Nowicka Danuta, Nowicki Michał
Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland.
Department of Anatomy, Poznan University of Medical Sciences, Poznań, Poland.
Acta Biochim Pol. 2016;63(1):131-138. doi: 10.18388/abp.2015_1105. Epub 2016 Feb 1.
The mechanism of steroid resistance in children with the nephrotic syndrome is yet unknown. About 20% of patients demonstrate steroid unresponsiveness and progress to end stage renal disease. Aberrant SOCS3 and SOCS5 expression in steroid resistant and sensitive patients has previously been demonstrated. Here, we investigate genetic and epigenetic mechanisms of regulation of SOCS3 and SOCS5 transcription in nephrotic children.
76 patients with the nephrotic syndrome (40 steroid resistant and 36 steroid sensitive) and 33 matched controls were included in this study. We performed genotyping of a total of 34 single nucleotide polymorphisms for SOCS3 and SOCS5 promoters and evaluated their methylation status using MS-PCR and QMSP methods.
Steroid resistant patients had a significantly lower methylation of one region of SOCS3 promoter in comparison with steroid sensitive patients and controls (p < 0.0001). However, the relative methylation level in the steroid sensitive patients and controls differed significantly even before the first steroid dose (p = 0.001758). Other SOCS3 and SOCS5 promoter regions displayed no differences in methylation or were fully methylated/unmethylated in all study groups, showing site-specific methylation. The allele and genotype distribution for SOCS3 and SOCS5 markers did not differ statistically between the groups.
We demonstrate an epigenetic mechanism of SOCS3 up-regulation in steroid resistant children with the nephrotic syndrome. The assessment of methylation/unmethylation of SOCS3 promoter might be an early marker for steroid responsiveness in NS patients.
儿童肾病综合征中类固醇抵抗的机制尚不清楚。约20%的患者表现出类固醇无反应性，并进展至终末期肾病。先前已证明类固醇抵抗和敏感患者中存在异常的SOCS3和SOCS5表达。在此，我们研究肾病儿童中SOCS3和SOCS5转录调控的遗传和表观遗传机制。
本研究纳入了76例肾病综合征患者（40例类固醇抵抗患者和36例类固醇敏感患者）以及33例匹配的对照。我们对SOCS3和SOCS5启动子的总共34个单核苷酸多态性进行了基因分型，并使用MS-PCR和QMSP方法评估了它们的甲基化状态。
与类固醇敏感患者和对照相比，类固醇抵抗患者的SOCS3启动子一个区域的甲基化水平显著降低（p < 0.0001）。然而，即使在首次使用类固醇之前，类固醇敏感患者和对照中的相对甲基化水平也存在显著差异（p = 0.001758）。其他SOCS3和SOCS5启动子区域在甲基化方面没有差异，或者在所有研究组中均为完全甲基化/未甲基化，表现出位点特异性甲基化。SOCS3和SOCS5标记的等位基因和基因型分布在各组之间没有统计学差异。
我们证明了肾病综合征类固醇抵抗儿童中SOCS3上调的表观遗传机制。评估SOCS3启动子的甲基化/未甲基化可能是NS患者类固醇反应性的早期标志物。
