妊娠期糖耐量受损与Ghrelin基因多态性及相关细胞因子水平的关联性研究
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摘要
妊娠期糖耐量受损(gestational impaired glucose tolerance,GIGT)为早期的血糖稳态改变,是介于正常妊娠状态和妊娠期糖尿病的一种中间状态,且有可能转化为妊娠期糖尿病。其临床表现与妊娠期糖尿病类似,主要为妊娠期高血压、羊水过多、巨大儿等母婴并发症,更重要的是糖脂代谢紊乱。
目前研究发现位于3号染色体上的Ghrelin基因表达的蛋白影响葡萄糖的代谢平衡。本研究按照知情同意的原则,选择2008年11月到2009年11月在昆明医学院第一附属医院就诊的汉族孕妇196例为研究对象(其中妊娠期糖耐量受损(GIGT)组94例,糖耐量正常对照组102例),采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法对Ghrelin基因常见的10个多态性位点在两组之间的分布进行了分析,并构建单倍型。结果发现在两组人群中这些SNP没有显著性差异(P>0.05)。而单倍型SNP+408C—SNP+2488G—SNP+3056C, SNP+408A—SNP+2488G—SNP+3056C和SNP-1500G—SNP-1062G—SNP-994C—SNP-604G在两组中的分布则有明显的区别(P<0.05)。其中单倍型SNP+408C—SNP+2488G—SNP+3056C(OR=0.434)对GIGT起到保护作用,而携带单倍型SNP-1500G—SNP-1062G—SNP-994C—SNP-604G(OR=2.200)和SNP+408A—SNP+2488G—SNP+3056C(OR=1.769)的个体则对GIGT易感。GIGT与Ghrelin的单倍型密切相关,与单一的SNP却无关,其原因我们估计可能为具有不同单倍型的Ghrelin基因表达活性不同,而血浆中Ghrelin的浓度又与糖尿病显著相关。单一的SNP的改变则不能对GIGT这种多基因病造成显著的影响。
同时,我们对GIGT组及正常对照组各随机选取40人,采用Luminex液相芯片技术对脂肪细胞因子水平进行了检测,结果发现,血清中瘦素(Leptin)的表达水平在GIGT组与正常对照组之间有显著性差异(P<0.05),而白介素6(IL-6)、肿瘤坏死因子α(TNF-α)、单核细胞趋化蛋白1(MCP-1)在两组之间则无明显区别(P>0.05),这使瘦素水平成为GIGT的一个潜在标志物。瘦素的高水平表达引起胰岛素抵抗,而后者又是糖耐量异常的主要原因之一。
本研究的目的在于寻找与GIGT遗传易感性相关的基因及其表达的蛋白。我们的结果为GIGT的发病机制的进一步研究提供了的依据,也为预防和治疗GIGT提供了新靶点。
Gestational impaired glucose tolerance (GIGT) as an early change in blood glucose homeostasis, is the intermediate state between normal pregnancy and gestational diabetes. It could be converted into gestational diabetes. GIGT has a similar clinical presentation with gestational diabetes, such as gestational hypertension, hydramnios, macrosomia. Moreover, GIGT cause disturbance of glucose metabolism and lipid metabolism.
It has been reported that the protein expression of Ghrelin gene located in Chromosome 3 affects glucose metabolism in balance. In accordance with the principle of informed consent, we choice 196 Han pregnant women who came from the First Affiliated Hospital of Kunming Medical College from November 2008 to November 2009 for the study(including two groups:94 patients with gestational impaired glucose tolerance and 102 normal glucose tolerance women). We assessed common genetic variation of the Ghrelin (ten single nucleotide polymorphisms) in the two groups by the restriction fragment length polymorphism method. In addition, haplotype assays were conducted. The genotype distributions of these ten common polymorphisms in gestational impaired glucose tolerance patients were no significant difference from those of normal controls (P>0.05), and the haplotypes (SNP-1500G—SNP-1062G—SNP-994C—SNP-604G; SNP+408C—SNP+2488G—SNP+3056C; SNP+408A—SNP+2488G—SNP+3056C) of the Ghrelin gene was found to be significantly associated with it (P<0.05). SNP+408C—SNP+2488G—SNP+3056C showed a protective role in gestational impaired glucose tolerance, and SNP-1500G—SNP-1062G—SNP-994C—SNP-604G,SNP+408A—SNP+2488G—SNP+3056C showed susceptible. The haplotypes of the Ghrelin gene was associated with gestational impaired glucose tolerance, and the SNPs was not. The reason of the above condition is that we estimate different haplotypes has different expression activity, and plasma Ghrelin concentration has significantly associated with diabetes. Changes in a single SNP can not have a significant impact.on multi-gene disease such as impaired glucose tolerance.
At the same time we randomly select 40 samples in each of the impaired glucose tolerance group and the control group, using Luminex multiplex analysis for the detection of cytokines Level. The results showed that the serum Leptin level has significant difference between GIGT group and control group (P<0.05), and interleukin 6 (IL-6), tumor necrosis factor a (TNF-a), monocyte chemoattractant protein 1 (MCP-1) have no obvious difference between the two groups (P>0.05). It makes Leptin as a potential marker for gestational impaired glucose tolerance. The high level of expression of Leptin cause insulin resistance, while the latter is one of the major reason for abnormal glucose tolerance.
The main purpose of the thesis is to find genes and their protein expression which is associated with GIGT, our results provide a basis for the GIGT further study of pathogenesis, and also provide a new target for prevention and treatment of gestational impaired glucose tolerance.
目前研究发现位于3号染色体上的Ghrelin基因表达的蛋白影响葡萄糖的代谢平衡。本研究按照知情同意的原则,选择2008年11月到2009年11月在昆明医学院第一附属医院就诊的汉族孕妇196例为研究对象(其中妊娠期糖耐量受损(GIGT)组94例,糖耐量正常对照组102例),采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法对Ghrelin基因常见的10个多态性位点在两组之间的分布进行了分析,并构建单倍型。结果发现在两组人群中这些SNP没有显著性差异(P>0.05)。而单倍型SNP+408C—SNP+2488G—SNP+3056C, SNP+408A—SNP+2488G—SNP+3056C和SNP-1500G—SNP-1062G—SNP-994C—SNP-604G在两组中的分布则有明显的区别(P<0.05)。其中单倍型SNP+408C—SNP+2488G—SNP+3056C(OR=0.434)对GIGT起到保护作用,而携带单倍型SNP-1500G—SNP-1062G—SNP-994C—SNP-604G(OR=2.200)和SNP+408A—SNP+2488G—SNP+3056C(OR=1.769)的个体则对GIGT易感。GIGT与Ghrelin的单倍型密切相关,与单一的SNP却无关,其原因我们估计可能为具有不同单倍型的Ghrelin基因表达活性不同,而血浆中Ghrelin的浓度又与糖尿病显著相关。单一的SNP的改变则不能对GIGT这种多基因病造成显著的影响。
同时,我们对GIGT组及正常对照组各随机选取40人,采用Luminex液相芯片技术对脂肪细胞因子水平进行了检测,结果发现,血清中瘦素(Leptin)的表达水平在GIGT组与正常对照组之间有显著性差异(P<0.05),而白介素6(IL-6)、肿瘤坏死因子α(TNF-α)、单核细胞趋化蛋白1(MCP-1)在两组之间则无明显区别(P>0.05),这使瘦素水平成为GIGT的一个潜在标志物。瘦素的高水平表达引起胰岛素抵抗,而后者又是糖耐量异常的主要原因之一。
本研究的目的在于寻找与GIGT遗传易感性相关的基因及其表达的蛋白。我们的结果为GIGT的发病机制的进一步研究提供了的依据,也为预防和治疗GIGT提供了新靶点。
Gestational impaired glucose tolerance (GIGT) as an early change in blood glucose homeostasis, is the intermediate state between normal pregnancy and gestational diabetes. It could be converted into gestational diabetes. GIGT has a similar clinical presentation with gestational diabetes, such as gestational hypertension, hydramnios, macrosomia. Moreover, GIGT cause disturbance of glucose metabolism and lipid metabolism.
It has been reported that the protein expression of Ghrelin gene located in Chromosome 3 affects glucose metabolism in balance. In accordance with the principle of informed consent, we choice 196 Han pregnant women who came from the First Affiliated Hospital of Kunming Medical College from November 2008 to November 2009 for the study(including two groups:94 patients with gestational impaired glucose tolerance and 102 normal glucose tolerance women). We assessed common genetic variation of the Ghrelin (ten single nucleotide polymorphisms) in the two groups by the restriction fragment length polymorphism method. In addition, haplotype assays were conducted. The genotype distributions of these ten common polymorphisms in gestational impaired glucose tolerance patients were no significant difference from those of normal controls (P>0.05), and the haplotypes (SNP-1500G—SNP-1062G—SNP-994C—SNP-604G; SNP+408C—SNP+2488G—SNP+3056C; SNP+408A—SNP+2488G—SNP+3056C) of the Ghrelin gene was found to be significantly associated with it (P<0.05). SNP+408C—SNP+2488G—SNP+3056C showed a protective role in gestational impaired glucose tolerance, and SNP-1500G—SNP-1062G—SNP-994C—SNP-604G,SNP+408A—SNP+2488G—SNP+3056C showed susceptible. The haplotypes of the Ghrelin gene was associated with gestational impaired glucose tolerance, and the SNPs was not. The reason of the above condition is that we estimate different haplotypes has different expression activity, and plasma Ghrelin concentration has significantly associated with diabetes. Changes in a single SNP can not have a significant impact.on multi-gene disease such as impaired glucose tolerance.
At the same time we randomly select 40 samples in each of the impaired glucose tolerance group and the control group, using Luminex multiplex analysis for the detection of cytokines Level. The results showed that the serum Leptin level has significant difference between GIGT group and control group (P<0.05), and interleukin 6 (IL-6), tumor necrosis factor a (TNF-a), monocyte chemoattractant protein 1 (MCP-1) have no obvious difference between the two groups (P>0.05). It makes Leptin as a potential marker for gestational impaired glucose tolerance. The high level of expression of Leptin cause insulin resistance, while the latter is one of the major reason for abnormal glucose tolerance.
The main purpose of the thesis is to find genes and their protein expression which is associated with GIGT, our results provide a basis for the GIGT further study of pathogenesis, and also provide a new target for prevention and treatment of gestational impaired glucose tolerance.
引文
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