本文選題：IGFBP7 + 代謝綜合征�。� 參考：《浙江大學(xué)》2017年博士論文

【摘要】：研究背景及目的代謝綜合征(Metabolic syndrome,MetS)是由高血糖、肥胖、血脂異常和高血壓等聚集發(fā)病的臨床征候群,是一組在代謝上相互關(guān)聯(lián)的危險(xiǎn)因素的組合,并且會(huì)增加糖尿病、心血管疾病、中風(fēng)和某些癌癥的發(fā)病風(fēng)險(xiǎn)。代謝綜合征及其相關(guān)慢性病的防治研究已成為我國(guó)疾病控制最重要內(nèi)容之一。胰島素抵抗(insulin resistance,IR)是代謝綜合征及其相關(guān)慢性病發(fā)生、發(fā)展過程中共同的病理生理基礎(chǔ)和最主要的發(fā)病機(jī)制。近年來研究發(fā)現(xiàn),胰島素樣生長(zhǎng)因子結(jié)合蛋白7(IGFBP7)能與胰島素高親和力的結(jié)合,對(duì)胰島素的生物學(xué)效應(yīng)產(chǎn)生影響,可能與胰島素抵抗的發(fā)生有關(guān)。同時(shí),代謝綜合征和胰島素抵抗的遺傳度在30%到50%之間,胰島素抵抗的發(fā)生與發(fā)展也受到遺傳因素的調(diào)控。因此,我們假設(shè),IGFBP7的遺傳變異調(diào)控了基因的表達(dá)與功能,并與胰島素抵抗和代謝綜合征的發(fā)生有關(guān)。本研究擬在橫斷面人群調(diào)查的基礎(chǔ)上通過病例-對(duì)照研究探討血清IGFBP7蛋白水平與胰島素抵抗和代謝綜合征的關(guān)系,揭示IGFBP7基因的遺傳變異在胰島素抵抗和代謝綜合征發(fā)生中的作用。研究結(jié)果提出了胰島素抵抗和代謝綜合征新的發(fā)病機(jī)制的闡釋,為代謝綜合征的防治提供了依據(jù)。材料與方法本研究擬在橫斷面人群中進(jìn)行流行病學(xué)調(diào)查,檢測(cè)血清IGFBP7蛋白的含量、以HOMA-IR指數(shù)評(píng)價(jià)胰島素敏感性,采用病例對(duì)照的研究方法探討血清IGFBP7蛋白與胰島素抵抗和代謝綜合征的關(guān)系;篩查與血清IGFBP7蛋白相關(guān)的SNPs,結(jié)合eQTL數(shù)據(jù)庫(kù),尋找調(diào)控IGFBP7基因表達(dá)的SNPs(Expression SNP,eSNP);分析IGFBP7基因的遺傳變異與MetS和IR發(fā)病風(fēng)險(xiǎn)的關(guān)聯(lián),在SNP-表型數(shù)據(jù)庫(kù)中進(jìn)行重復(fù),篩選與代謝綜合征和胰島素抵抗相關(guān)的IGFBP7SNPs(PhenoSNP,phSNP);在eSNPs和phSNPs中篩選與基因表達(dá)和疾病表型相關(guān)性一致的SNPs;對(duì)這些SNPs,觀察在校正血清IGFB7蛋白水平前后,與MetS和IR的關(guān)聯(lián)的變化,以此篩選通過調(diào)控IGFBP7基因表達(dá)來影響代謝綜合征和胰島素抵抗的發(fā)生的SNPs。研究結(jié)果本研究發(fā)現(xiàn)代謝綜合征患者的血清IGFBP7蛋白中位數(shù)水平為45.80 ng/ml(四分位數(shù)間距P25、P75:36.50,59.05)顯著高于對(duì)照組的35.80 ng/ml(28.70,46.40)(P0.001);胰島素抵抗組的血清IGFBP7蛋白的中位數(shù)水平為40.45 ng/ml(31.83,52.45),高于胰島素敏感組的 38.25 ng/ml(30.30,50.53)(P0.001);高血清IGFBP7蛋白水平(≥35.80 ng/ml)人群的代謝綜合征患病風(fēng)險(xiǎn)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蛋白水平人群胰島素抵抗的患病風(fēng)險(xiǎn)是低蛋白IGFBP7人群的 1.240 倍(OR = 1.240,9 95%CI = 1.055-1.458)。血清 IGFBP7 蛋白水平與高密度脂蛋白膽固醇(HDL-C)、低密度脂蛋白膽固醇(LDL-C)、腰臀比(WHR)相關(guān)。rs4865174和rs13141016突變型等位基因攜帶者的血清IGFBP7蛋白水平低于野生型等位基因的攜帶者(rs4865174:β=-0.023,P=0.027;rs13141016:β=-0.011,P=0.044);GTEx數(shù)據(jù)顯示,rs13141016在成纖維細(xì)胞、內(nèi)臟網(wǎng)膜脂肪、全血、乳腺、皮下脂肪中與mRNA轉(zhuǎn)錄水平相關(guān),rs4865174與心臟組織中的mRNA轉(zhuǎn)錄水平相關(guān);與野生型等位基因的攜帶者相比,rs4865174(β=-0.037,P=0.031)和 rs13141016(β =-0.019,P=0.042)的突變型等位基因的攜帶者患代謝綜合征和胰島素抵抗的風(fēng)險(xiǎn)降低;MAGIC數(shù)據(jù)庫(kù)表示,rs4865174和rs13141016與胰島素水平相關(guān);rs4865174和rs13141016與代謝綜合征和胰島素抵抗的顯著關(guān)聯(lián)在校正血清IGFBP7蛋白后不具有統(tǒng)計(jì)學(xué)意義;功能預(yù)測(cè)發(fā)現(xiàn)rs4865174和rs13141016可能通過影響該基因的轉(zhuǎn)錄因子結(jié)合能力來調(diào)控基因表達(dá),并且 rs13141016 位于 Elite enhancer GH04F057070 區(qū)域內(nèi),說明 rs4865174和rs13141016可能通過影響轉(zhuǎn)錄因子結(jié)合序列或者影響增強(qiáng)子效應(yīng)來調(diào)控基因的表達(dá),并與代謝綜合征和胰島素抵抗有關(guān)。研究結(jié)論血清IGFBP7蛋白水平與MetS和IR相關(guān)。IGFBP7基因的遺傳變異可通過調(diào)控蛋白表達(dá)的方式影響MetS和IR的發(fā)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.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R589

【參考文獻(xiàn)】

相關(guān)期刊論文 前2條

1 ;Science Letters:IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis with its expression associated with DNA hypomethylation of exon 1[J];Journal of Zhejiang University Science(Life Science);2006年11期

2 顧東風(fēng),Reynolds K,楊文杰,陳恕鳳,吳錫桂,段秀芳,蒲曉東,徐麗華,吳先萍,陳祥福,魏仁敏,陳娜縈,吳天一,王禮桂,姚才良,牟建軍,馬義峰,王曉飛,Whelton P,何江;中國(guó)成年人代謝綜合征的患病率[J];中華糖尿病雜志;2005年03期

，

本文編號(hào)：1809016