Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Osteoarthritis Cartilage. 2010 Jun;18(6):817-24. doi: 10.1016/j.joca.2010.02.004. Epub 2010 Feb 21.
Kashin-Beck disease (KBD) is a disabling osteoarthropathy involving growth cartilage endemic to selenium (Se)-deficient regions in China. Associations between genetic variation in selenoprotein genes and susceptibility to many diseases have recently been investigated but few studies have been performed on KBD. We found four genetic polymorphisms in selenoprotein genes and assessed their association with increased susceptibility to KBD.
Four polymorphisms including GPX1 (rs1050450), TrxR2 (rs5748469), SEPP1 (rs7579) and DIO2 (rs225014) were analyzed for 161 KBD patients and 312 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or tetra-primer amplification refractory mutation system PCR (Tetra-primer ARMS PCR). Glutathione peroxidase (GPX) activity in whole blood was measured using a GPX assay kit. The mRNA expression of GPX1, nuclear factor-kappaB (NF-kappaB) p65 and p53 in both whole blood and articular cartilage tissue were detected using Real-Time PCR.
The genotypic and allelic frequency of GPX1 Pro198Leu was significantly different between KBD patients and controls (P=0.013, P=0.037). A significant increased KBD risk was observed in individuals with Pro/Leu or Leu/Leu (odds ratio=1.781; 95% confidence interval: 1.127-2.814) compared with Pro/Pro. No association was observed between the other three single nucleotide polymorphisms (SNPs) and KBD risk. In addition, GPX enzyme activity in whole blood was lower in the KBD group (P<0.01), and the GPX activity in whole blood decreased significantly in a subgroup of individuals representing Pro/Leu and Leu/Leu compared to Pro/Pro (P<0.01). In whole blood and articular cartilage tissue samples of KBD patients, GPX1 and NF-kappaB p65 mRNA levels were lower (P<0.01) while p53 levels were higher (P<0.001).
GPX1 Pro198Leu is a potential genetic risk factor in the development of KBD and the GPX1 Leu allele is significantly associated with higher KBD risk among the Chinese Han population and with lower GPX enzyme activity. The expression of apoptosis related molecules in KBD patients significantly differs from controls.
大骨节病（KBD）是一种累及生长软骨的致残性骨关节炎，流行于中国硒（Se）缺乏地区。最近，人们对硒蛋白基因的遗传变异与许多疾病的易感性之间的关系进行了研究，但对 KBD 的研究很少。我们发现了硒蛋白基因中的四个遗传多态性，并评估了它们与 KBD 易感性增加的关系。
使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）或四引物扩增受阻突变系统 PCR（Tetra-primer ARMS PCR）分析了 161 例 KBD 患者和 312 例对照中的四个多态性，包括 GPX1（rs1050450）、TrxR2（rs5748469）、SEPP1（rs7579）和 DIO2（rs225014）。使用 GPX 测定试剂盒测量全血中的谷胱甘肽过氧化物酶（GPX）活性。使用实时 PCR 检测全血和关节软骨组织中 GPX1、核因子-κB（NF-κB）p65 和 p53 的 mRNA 表达。
KBD 患者和对照组之间 GPX1 Pro198Leu 的基因型和等位基因频率存在显著差异（P=0.013，P=0.037）。与 Pro/Pro 相比，Pro/Leu 或 Leu/Leu 的个体患 KBD 的风险显著增加（比值比=1.781；95%置信区间：1.127-2.814）。其他三个单核苷酸多态性（SNP）与 KBD 风险无关。此外，KBD 组全血中的 GPX 酶活性较低（P<0.01），Pro/Leu 和 Leu/Leu 亚组的全血 GPX 活性明显低于 Pro/Pro（P<0.01）。在 KBD 患者的全血和关节软骨组织样本中，GPX1 和 NF-κB p65 mRNA 水平较低（P<0.01），而 p53 水平较高（P<0.001）。
GPX1 Pro198Leu 是 KBD 发病的潜在遗传危险因素，Leu 等位基因与中国汉族人群中更高的 KBD 风险显著相关，与更低的 GPX 酶活性相关。KBD 患者中与细胞凋亡相关的分子表达与对照组明显不同。
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