IGFBP7与代谢综合征及胰岛素抵抗的关联研究

发布时间：2018-04-27 03:35

本文选题：IGFBP7 + 代谢综合征　；参考：《浙江大学》2017年博士论文

【摘要】：研究背景及目的代谢综合征(Metabolic syndrome,MetS)是由高血糖、肥胖、血脂异常和高血压等聚集发病的临床征候群,是一组在代谢上相互关联的危险因素的组合,并且会增加糖尿病、心血管疾病、中风和某些癌症的发病风险。代谢综合征及其相关慢性病的防治研究已成为我国疾病控制最重要内容之一。胰岛素抵抗(insulin resistance,IR)是代谢综合征及其相关慢性病发生、发展过程中共同的病理生理基础和最主要的发病机制。近年来研究发现,胰岛素样生长因子结合蛋白7(IGFBP7)能与胰岛素高亲和力的结合,对胰岛素的生物学效应产生影响,可能与胰岛素抵抗的发生有关。同时,代谢综合征和胰岛素抵抗的遗传度在30%到50%之间,胰岛素抵抗的发生与发展也受到遗传因素的调控。因此,我们假设,IGFBP7的遗传变异调控了基因的表达与功能,并与胰岛素抵抗和代谢综合征的发生有关。本研究拟在横断面人群调查的基础上通过病例-对照研究探讨血清IGFBP7蛋白水平与胰岛素抵抗和代谢综合征的关系,揭示IGFBP7基因的遗传变异在胰岛素抵抗和代谢综合征发生中的作用。研究结果提出了胰岛素抵抗和代谢综合征新的发病机制的阐释,为代谢综合征的防治提供了依据。材料与方法本研究拟在横断面人群中进行流行病学调查,检测血清IGFBP7蛋白的含量、以HOMA-IR指数评价胰岛素敏感性,采用病例对照的研究方法探讨血清IGFBP7蛋白与胰岛素抵抗和代谢综合征的关系;筛查与血清IGFBP7蛋白相关的SNPs,结合eQTL数据库,寻找调控IGFBP7基因表达的SNPs(Expression SNP,eSNP);分析IGFBP7基因的遗传变异与MetS和IR发病风险的关联,在SNP-表型数据库中进行重复,筛选与代谢综合征和胰岛素抵抗相关的IGFBP7SNPs(PhenoSNP,phSNP);在eSNPs和phSNPs中筛选与基因表达和疾病表型相关性一致的SNPs;对这些SNPs,观察在校正血清IGFB7蛋白水平前后,与MetS和IR的关联的变化,以此筛选通过调控IGFBP7基因表达来影响代谢综合征和胰岛素抵抗的发生的SNPs。研究结果本研究发现代谢综合征患者的血清IGFBP7蛋白中位数水平为45.80 ng/ml(四分位数间距P25、P75:36.50,59.05)显著高于对照组的35.80 ng/ml(28.70,46.40)(P0.001);胰岛素抵抗组的血清IGFBP7蛋白的中位数水平为40.45 ng/ml(31.83,52.45),高于胰岛素敏感组的 38.25 ng/ml(30.30,50.53)(P0.001);高血清IGFBP7蛋白水平(≥35.80 ng/ml)人群的代谢综合征患病风险是低血清IGFBP7 蛋白水平(35.80 ng/ml)人群的 2.758 倍(OR = 2.758,95%CI = 2.308-3.297),高血清IGFBP7蛋白水平人群胰岛素抵抗的患病风险是低蛋白IGFBP7人群的 1.240 倍(OR = 1.240,9 95%CI = 1.055-1.458)。血清 IGFBP7 蛋白水平与高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、腰臀比(WHR)相关。rs4865174和rs13141016突变型等位基因携带者的血清IGFBP7蛋白水平低于野生型等位基因的携带者(rs4865174:β=-0.023,P=0.027;rs13141016:β=-0.011,P=0.044);GTEx数据显示,rs13141016在成纤维细胞、内脏网膜脂肪、全血、乳腺、皮下脂肪中与mRNA转录水平相关,rs4865174与心脏组织中的mRNA转录水平相关;与野生型等位基因的携带者相比,rs4865174(β=-0.037,P=0.031)和 rs13141016(β =-0.019,P=0.042)的突变型等位基因的携带者患代谢综合征和胰岛素抵抗的风险降低;MAGIC数据库表示,rs4865174和rs13141016与胰岛素水平相关;rs4865174和rs13141016与代谢综合征和胰岛素抵抗的显著关联在校正血清IGFBP7蛋白后不具有统计学意义;功能预测发现rs4865174和rs13141016可能通过影响该基因的转录因子结合能力来调控基因表达,并且 rs13141016 位于 Elite enhancer GH04F057070 区域内,说明 rs4865174和rs13141016可能通过影响转录因子结合序列或者影响增强子效应来调控基因的表达,并与代谢综合征和胰岛素抵抗有关。研究结论血清IGFBP7蛋白水平与MetS和IR相关。IGFBP7基因的遗传变异可通过调控蛋白表达的方式影响MetS和IR的发生。
[Abstract]:Background and objective Metabolic syndrome (MetS) is a group of clinical symptoms associated with hyperglycemia, obesity, dyslipidemia, and hypertension. It is a combination of metabolic risk factors and increases the risk of diabetes, cardiovascular disease, stroke, and certain cancers. Metabolic syndrome and its syndrome The prevention and control of related chronic diseases has become one of the most important content of disease control in China. Insulin resistance (IR) is a common pathophysiological basis and the most important pathogenesis in the development of metabolic syndrome and related chronic diseases. In recent years, insulin like growth factor binding protein 7 (IGFBP7) has been found. The combination of high affinity with insulin and the biological effects of insulin may be associated with insulin resistance. The heritability of metabolic syndrome and insulin resistance is between 30% and 50%, and the development and development of insulin resistance are also regulated by genetic factors. Therefore, we hypothesize that the genetic variation of IGFBP7 The expression and function of genes are regulated and related to insulin resistance and metabolic syndrome. This study intends to investigate the relationship between serum IGFBP7 protein level and insulin resistance and metabolic syndrome by a case-control study on the basis of a cross-sectional population survey, and to reveal the genetic variation of the IGFBP7 gene in insulin resistance and metabolism. The results of the study suggest the new pathogenesis of insulin resistance and metabolic syndrome, providing a basis for the prevention and treatment of metabolic syndrome. Materials and methods this study is to conduct epidemiological investigations in a cross-sectional population, detect the content of serum IGFBP7 protein, and evaluate insulin sensitivity with the HOMA-IR index. A case-control study was used to investigate the relationship between serum IGFBP7 protein and insulin resistance and metabolic syndrome; to screen the SNPs associated with serum IGFBP7 protein and to search for SNPs (Expression SNP, eSNP) to regulate the expression of IGFBP7 gene combined with the eQTL database; and to analyze the association between the genetic variation of the IGFBP7 gene and the risk of MetS and IR. Repeat in the P- phenotypic database to screen IGFBP7SNPs (PhenoSNP, phSNP) associated with metabolic syndrome and insulin resistance; select SNPs in eSNPs and phSNPs that are consistent with the correlation of gene expression and disease phenotype; for these SNPs, the changes in the association with MetS and IR before and after the correction of the serum level of IGFB7 protein are screened through this method. The results of SNPs. study on the regulation of IGFBP7 gene expression in metabolic syndrome and insulin resistance found that the median level of serum IGFBP7 protein in the patients with metabolic syndrome was 45.80 ng/ml (four quantile spacing P25, P75:36.50,59.05) was significantly higher than that of the control group of 35.80 ng/ml (28.70,46.40) (P0.001), and insulin resistance group. The median level of serum IGFBP7 protein was 40.45 ng/ml (31.83,52.45), higher than 38.25 ng/ml (30.30,50.53) in insulin sensitive group (30.30,50.53) (P0.001); the risk of metabolic syndrome in high serum IGFBP7 protein level (> 35.80 ng/ml) was 2.758 times that of the low serum IGFBP7 protein level (35.80 ng/ml) (OR = 2.758,95%CI =) The risk of insulin resistance in people with high serum IGFBP7 protein levels was 1.240 times as high as that of the low protein IGFBP7 population (OR = 1.240,9 95%CI = 1.055-1.458). Serum IGFBP7 protein levels were associated with high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), waist to hip ratio (WHR) related.Rs4865174 and rs13141016 process variants. The level of serum IGFBP7 protein in the carrier was lower than that of the carriers of the wild type allele (rs4865174: beta =-0.023, P=0.027; rs13141016: beta =-0.011, P=0.044); GTEx data showed that rs13141016 was associated with the transcription of mRNA in fibroblasts, visceral omentum fat, whole blood, breast, and subcutaneous fat, and rs4865174 and transcriptional water in the heart tissue. The carriers of the mutant alleles of rs4865174 (beta =-0.037, P=0.031) and rs13141016 (beta =-0.019, P=0.042) had a lower risk of metabolic syndrome and insulin resistance compared with the carriers of the wild type allele; the MAGIC database indicated that rs4865174 and rs13141016 were associated with insulin levels; rs4865174 and rs13141016 and generations. The significant association of the Xie syndrome and insulin resistance is not statistically significant after the correction of the serum IGFBP7 protein; functional prediction shows that rs4865174 and rs13141016 may regulate gene expression by influencing the transcription factor binding ability of the gene, and rs13141016 is located in the Elite enhancer GH04F057070 region, indicating rs4865174 and RS. 13141016 may regulate gene expression by influencing transcription factor binding sequence or influence enhancer effect, and is related to metabolic syndrome and insulin resistance. The study concluded that the genetic variation of serum IGFBP7 protein level and MetS and IR related.IGFBP7 gene can affect the occurrence of MetS and IR by regulating the expression of protein.

【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R589

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