青少年的成年起病型糖尿病及糖尿病周围神经病变的分子遗传学研究

发布时间：2018-03-07 07:44

本文选题：青少年的成年起病型糖尿病5型　切入点：大片段缺失和重复　出处：《上海交通大学》2015年硕士论文　论文类型：学位论文

【摘要】：糖尿病是一种由遗传与环境因素共同参与并相互作用的疾病,其发生发展的分子遗传学机制尚未阐明。此外,不同种族间糖尿病的遗传易感性存在差异。因而本论文在中国人群中开展糖尿病病因学探索,一方面聚焦于青少年的成年起病型糖尿病5型,探讨肝细胞核因子1β基因大片段缺失、重复在中国汉族特殊糖尿病人群中的发生情况。另一方面,聚焦于糖尿病周围神经病变,探讨中国人2型糖尿病易感位点与外周神经功能的相关性。本论文的主要内容与结果如下:1.中国汉族特殊糖尿病人群中肝细胞核因子1β基因大片段缺失、重复筛查研究本研究旨在运用多重连接探针扩增技术(Multiplex Ligation-dependent Probe Amplification,MLPA)对糖尿病伴肾脏功能异常和/或肾脏结构异常的患者进行大片段缺失、重复筛查和临床表型研究。了解上海及其周边地区肝细胞核因子1β(hepatocyte nuclear factor 1β,HNF-1β)基因大片段缺失、重复发生情况。入选101例糖尿病伴肾脏结构异常和/或肾功能受损的患者(直接测序法未检测出存在肝细胞核因子1β基因突变),运用MLPA技术进行HNF-1β基因大片段缺失、重复筛查,并进行临床表型分析。结果显示,在糖尿病伴肾脏结构异常和/或肾功能受损的患者中发现1例多发肾囊肿伴右肾发育不全、双子宫、胰腺体尾部萎缩患者存在HNF-1β整个基因杂合性缺失。该患者在糖尿病与肾病病情或是其他临床表现上,与HNF-1β基因点突变患者无明显差异,使用胰岛素后血糖水平处于可控状态,且其治疗方案与部分点突变患者相似,除了在糖尿病诊断年龄上早于点突变患者的平均年龄。HNF-1β基因大片段缺失在中国上海及其周边地区特殊类型糖尿病人群中发生率较低,约占临床表型疑似青少年的成年起病型糖尿病5型(Maturity onset diabetes of the young 5,MODY5)患者的1%。2.中国人2型糖尿病易感位点与外周神经功能的关联研究本研究探讨中国人2型糖尿病易感位点与中国汉族2型糖尿病患者外周神经功能的相关性。入选1900例2型糖尿病患者,对所有受试者进行神经传导检查来评估其外周神经功能。选取10个中国人2型糖尿病易感位点PPARG-rs1801282、IGF2BP2-rs7651090、CDKAL1-rs7756992、CDKN2A/2B-rs10811661、IDE-KIF11-HHEX-rs1111875、TCF7L2-rs7903146、HNF1β-rs4430796、KCNQ1-rs2237892、SLC30A8-rs13266634和KCNJ11-rs5219,用基质辅助激光解析电离飞行时间质谱的方法对其进行基因型分型。研究发现,在2型糖尿病人群中,KCNJ11-rs5219(E23K)和与神经传导检查各参数存在相关性,校正年龄、2型糖尿病病程及Hb A1c后,结果显示:传导速度Z-score:β:0.113,P=0.01;波幅Z-score:β:0.133,P=0.01;潜伏期Z-score:β:-0.116,P=0.01;总Z-score:β:0.106,P=0.036。CDKAL1-rs7756992和TCF7L2-rs7903146与波幅Z-score存在相关性(校正年龄、病程及Hb A1c后P值分别为0.028和0.016),但与传导速度Z-score(校正年龄、病程及Hb A1c后P值分别为0.393和0.281)及潜伏期Z-score(校正年龄、病程及Hb A1c后P值分别为0.286和0.273)不存在相关性。其余7个单核苷酸多态性(single nucleotide polymorphism,SNP)位点与外周神经功能间不存在显著的相关性。因此,本研究结果表明在中国2型糖尿病人群中,KCNJ11基因多态性位点rs5219与外周神经功能密切相关。2型糖尿病与糖尿病周围神经病变存在共同的遗传因素。
[Abstract]:Diabetes is a combination of genetic and environmental factors involved in the interaction of disease and molecular genetics, the occurrence and development mechanism has not been elucidated. In addition, there are genetic susceptibility to different racial differences. The diabetes in China groups to carry out diabetes etiology exploration, a focus on young adult onset type 5 diabetes mellitus. To investigate the hepatocyte nuclear factor 1 gene deletion, repeat in Chinese Han special diabetic population in the situation. On the other hand, focusing on diabetic peripheral neuropathy, to explore the relationship between the Chinese susceptibility loci and peripheral nerve function in type 2 diabetes. The main contents of this paper and the results are as follows: Hepatocyte nuclear factor 1. Chinese Han special diabetes 1 beta gene deletion, repeat screening of this research aims at the application of multiplex ligation dependent probe amplification (Multiple X Ligation-dependent Probe Amplification, MLPA) in diabetic patients with renal dysfunction and / or renal structural abnormalities in patients with large deletions, repeated screening and clinical phenotype research. Understanding of Shanghai and its surrounding areas hepatocyte nuclear factor 1 (hepatocyte nuclear factor 1 beta, beta HNF-1) gene deletion, repeat occurrence. In 101 diabetic patients with renal abnormalities and / or patients with impaired renal function (direct sequencing did not detect the presence of hepatocyte nuclear factor 1 gene mutation), using MLPA technology of HNF-1 beta gene deletion, repeat screening, and clinical phenotype analysis. The results showed that in renal structural abnormalities and / or renal function the damage was found in patients with 1 cases of multiple renal cyst with right renal hypoplasia, double uterus with diabetes, the body and tail of pancreas atrophy in patients with HNF-1 of the beta gene heterozygosity of the patients. In the condition of diabetes and nephropathy or other clinical manifestations, no significant difference between the patients and the mutation of HNF-1 beta gene, in a controllable state blood glucose level with insulin, and the treatment scheme and point mutations were similar, but the average age of.HNF-1 beta gene in the diagnosis of diabetes mellitus in early age point mutation in patients with large deletions in a special type of diabetes China in Shanghai and its surrounding areas with low incidence, accounting for clinical phenotype of suspected adult onset diabetes of the young type 5 (Maturity onset diabetes of the young 5, MODY5) correlation study of predisposing loci and peripheral nerve function in patients with 1%.2. Chinese type 2 diabetes in this study Chinese type 2 diabetes susceptibility loci and Chinese Han patients with type 2 diabetes peripheral nerve function. 1900 cases of patients with type 2 diabetes, nerve in all subjects To assess the peripheral nerve conduction function. Select 10 Chinese type 2 diabetes susceptibility loci PPARG-rs1801282, IGF2BP2-rs7651090, CDKAL1-rs7756992, CDKN2A/2B-rs10811661, IDE-KIF11-HHEX-rs1111875, TCF7L2-rs7903146, HNF1, KCNQ1-rs2237892, beta -rs4430796, SLC30A8-rs13266634 and KCNJ11-rs5219, using the method of matrix assisted laser desorption ionization time-of-flight mass spectrometry of genotypes on the type. The study found that in patients with type 2 diabetes, KCNJ11-rs5219 (E23K) and the correlation between the parameters and nerve conduction tests corrected for age, duration of type 2 diabetes and Hb A1c, showed that the conduction velocity of Z-score: beta 0.113, P=0.01; Z-score:: 0.133, P=0.01 amplitude beta; the latency of Z-score:: -0.116, P=0.01; total beta beta Z-score: 0.106, there is correlation between P=0.036.CDKAL1-rs7756992 and TCF7L2-rs7903146 and the amplitude of Z-score (adjusted for age, course of disease and Hb A1c P = 0.028 and 0.016), but with the conduction velocity of Z-score (adjusted for age, course of disease and Hb A1c P were 0.393 and 0.281) and Z-score (adjusted for age, duration of incubation and Hb A1c P were 0.286 and 0.273) there is no correlation. The other 7 SNPs (single nucleotide polymorphism, SNP) had no significant correlation with the site of peripheral nerve function. Therefore, the results of this study show that Chinese in patients with type 2 diabetes, there are common genetic factors KCNJ11 gene polymorphism sites of rs5219 and peripheral nerve function is closely related to type.2 diabetes and diabetic peripheral neuropathy.

【学位授予单位】：上海交通大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R587.2;R745

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