本文選題：糖尿病 + 糖尿病視網(wǎng)膜病變　； 參考：《重慶醫(yī)科大學(xué)》2016年博士論文

【摘要】：目的:糖尿病視網(wǎng)膜病變(diabetic retinopathy,DR)是一種較常見的糖尿病微血管并發(fā)癥之一,糖尿病病程、血糖水平、血壓、血脂等臨床因素對糖尿病視網(wǎng)膜病變的發(fā)生發(fā)展有一定的影響。但糖尿病視網(wǎng)膜病變在發(fā)病的病程、嚴重程度上卻存在很大的個體差異,這種差異性被認為是由于基因多態(tài)性造成的。本研究的目的是從臨床指標及基因多態(tài)性兩方面研究分析影響糖尿病視網(wǎng)膜病變發(fā)生發(fā)展的相關(guān)因素。材料方法:自2014年6月1日至2015年6月31日,參照相關(guān)診斷標準,在內(nèi)蒙古自治區(qū)人民醫(yī)院內(nèi)分泌科住院患者中收集糖尿病患者319例,同期在內(nèi)蒙古自治區(qū)人民醫(yī)院體檢中心收集正常人群對照387例。根據(jù)眼底熒光造影將糖尿病患者分為糖尿病不伴隨視網(wǎng)膜病變(NDR組)和糖尿病視網(wǎng)膜病變(DR組),DR組患者175例,NDR組患者144例。收集患者的樣本信息包括:一般信息:姓名、性別、年齡、民族、住院號、身份證號、身高、體重、體重指數(shù);臨床信息:糖尿病病程、既往病史、吸煙飲酒史、降糖藥和胰島素使用情況、有否糖尿病視網(wǎng)膜病變;生化指標:空腹血糖、糖化血紅蛋白、總膽固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白、血尿素氮、肌酐、尿白蛋白排泄率、腎小球濾過率、空腹C肽、胱抑素C。并以住院號或編號對應(yīng)樣本進行了數(shù)據(jù)資料整理。2.采用Pearson’s卡方檢驗分析分類變量的頻率分布在DR和NDR組間是否存在統(tǒng)計學(xué)差異,利用Welch’s t檢驗分析臨床指標(Duration ofdiabetes、bmi、fastingglucose、hba1c、totalcholesterol、triglycerides、ldlcholesterol、hdlcholesterol、gfr、cp、urea、cr、cys-c、ins)的均值在dr組和ndr組間是否存在統(tǒng)計學(xué)差異。選取23個單核苷酸多態(tài)性位點進行了糖尿病及糖尿病視網(wǎng)膜病變與遺傳易感性關(guān)聯(lián)分析研究。使用sequenommassarray基因分型技術(shù)進行snp分析,利用exacttest方法對對照組進行hardy-weinberg平衡檢驗;采用方差分析的方法分析糖尿病及糖尿病視網(wǎng)膜病變臨床指標的均值在不同位點的不同基因型下的差異。無條件logistics回歸方法計算風(fēng)險等位基因的相對優(yōu)勢比oddsratios和95%的置信區(qū)間,衡量這些突變等位基因與糖尿病及糖尿病視網(wǎng)膜病變的相關(guān)性。利用haploview和snpstats分析位于同一個基因上若干個位點的連鎖程度及單體型效應(yīng)。所有統(tǒng)計檢驗均為雙側(cè)概率檢驗,檢驗水準p=0.05。結(jié)果:采用pearson’s卡方檢驗分析發(fā)現(xiàn)胰島素治療在病例dr組和ndr組間的頻數(shù)分布存在統(tǒng)計學(xué)差異;welch’st檢驗分析年齡、durationofdiabetes、totalcholesterol、triglycerides、ldl、gfr、cp的均值在dr組和ndr組間存在統(tǒng)計學(xué)差異。采用方差分析的方法分析snp與糖尿病臨床指標之間的關(guān)系,發(fā)現(xiàn)在kiaa0825rs17376456和igf1rs6214位點的不同基因型下糖化血紅蛋白的均值存在統(tǒng)計學(xué)差異。在lekr1-ccnl1rs13064954和arhgap22rs4838605位點的不同基因型下甘油三脂的均值存在統(tǒng)計學(xué)差異。在糖尿病視網(wǎng)膜病變的分析結(jié)果發(fā)現(xiàn),mthfrrs1537516位點影響甘油三脂在不同基因型下的均值存在統(tǒng)計學(xué)差異,突變基因型的tg的均值顯著高于野生型的均值。還發(fā)現(xiàn)mthfr基因rs1537516位點影響糖尿病視網(wǎng)膜病變患者的胰島素水平;本研究還發(fā)現(xiàn)nos3rs3918227位點和ulekr1-ccnl1rs13064954位點的不同基因型下cys-c的均值存在統(tǒng)計學(xué)差異。在等位基因模型下,lekr1-ccnl1rs13064954位點由g等位基因突變成a等位基因時,糖尿病視網(wǎng)膜病變的患病風(fēng)險較糖尿病不伴隨視網(wǎng)膜病變的風(fēng)險降低了43%(or=0.57,95%ci:0.34-0.96,p=0.032)。采用邏輯回歸分析不同遺傳模型下,基因多態(tài)性對糖尿病視網(wǎng)膜病變遺傳易感性的影響。在經(jīng)過年齡和性別的校正后,log-additive模型下,igsf21-klhdc7ars3007729位點,攜帶t等位基因的個體較攜帶c等位基因個體糖尿病的發(fā)病風(fēng)險增加了26%(or=1.26,95%ci:1.01-1.56,p=0.037);在共顯性模型下,攜帶nos3rs1799983gt基因型的個體的發(fā)病風(fēng)險較攜帶gg基因型個體的糖尿病患病風(fēng)險增加了49%(or=1.49,95%ci:1.02-2.18,p=0.002),攜帶nos3rs3918227ca基因型的個體的發(fā)病風(fēng)險是攜帶cc基因型個體的糖尿病患病風(fēng)險的1.41倍(or=1.41,95%ci:0.91-2.20,p=0.046),攜帶arhgap22rs4838605tc基因型的個體的糖尿病患病風(fēng)險是攜帶tt基因型個體1.54倍(or=1.54,95%ci:1.06-2.24,p=0.003)采用邏輯回歸分析不同遺傳模型下,基因多態(tài)性對糖尿病視網(wǎng)膜病變遺傳易感性的影響。發(fā)現(xiàn)在沒有做任何修正時,在共顯性模型下,攜帶igsf21-klhdc7ars3007729tt基因型的個體的發(fā)病風(fēng)險是攜帶cc基因型個體的糖尿病視網(wǎng)膜病變患病風(fēng)險的2.11倍(or=2.11,95%ci:1.26-3.53,p=0.013);在log-additive模型下,lekr1-ccnl1rs13064954位點的等位基因由g突變成a時,糖尿病視網(wǎng)膜病變的患病風(fēng)險降低了42%(or=0.58,95%ci:0.34-0.96,p=0.034)結(jié)論:NOS3基因rs1799983和rs3918227和ARHGAP22 rs4838605基因多態(tài)性與糖尿病相關(guān);(1)LEKR1-CCNL1 rs13064954基因多態(tài)性與糖尿病患者的糖尿病視網(wǎng)膜病變相關(guān);(2)IGSF21-KLHDC7A rs3007729基因多態(tài)性與糖尿病和糖尿病患者的糖尿病視網(wǎng)膜病變相關(guān);(3)KIAA0825 rs17376456和IGF1 rs6214基因多態(tài)性與糖尿病患者的糖化血紅蛋白相關(guān);LEKR1-CCNL1 rs13064954和ARHGAP22rs4838605基因多態(tài)性與糖尿病患者的甘油三酯水平相關(guān)。(4)MTHFR rs1537516位點與糖尿病視網(wǎng)膜病變患者的甘油三脂和胰島素水平均相關(guān)。
[Abstract]:Objective: diabetic retinopathy (DR) is one of the most common diabetic microvascular complications. Clinical factors such as diabetes course, blood sugar level, blood pressure, blood lipid and other clinical factors have some influence on the development of diabetic retinopathy. But diabetic retinopathy is in the course of disease, but there is a serious degree of disease. This difference is considered to be caused by genetic polymorphism. The purpose of this study is to analyze the factors affecting the development of diabetic retinopathy from two aspects of clinical indicators and genetic polymorphisms. Material methods: from June 1, 2014 to June 31, 2015, in Inner Mongolia 319 Cases of diabetic patients were collected from the Department of endocrinology in the Department of Endocrinology, the people's Hospital of the ancient autonomous region. In the same period, 387 cases of normal people were collected at the medical center of the people's Hospital in the Inner Mongolia Autonomous Region. The diabetics were divided into diabetic retinopathy (group NDR) and diabetic retinopathy (group DR) according to fundus fluorescein angiography, and group DR was 175 For example, 144 patients in group NDR. Sample information included: name, sex, age, age, nationality, hospital number, ID number, height, weight, body mass index; clinical information: diabetes course, past history, smoking and drinking history, hypoglycemic and islet use, diabetic retinopathy; biochemical index: fasting blood sugar, Glycosylated hemoglobin, total cholesterol, triglycerides, low density lipoprotein, high density lipoprotein, blood urea nitrogen, creatinine, urinary albumin excretion, glomerular filtration rate, fasting C peptide, Cystatin C. and data sorting with the number of hospitalized or numbered samples for.2. Pearson 's chi square test analysis of the frequency distribution of the classification variables in DR Whether there is statistical difference between group NDR and NDR group, there are statistical differences between Duration ofdiabetes, BMI, fastingglucose, HbA1c, Totalcholesterol, triglycerides, Welch 't test, and select 23 single nucleotide polymorphisms. The relationship between diabetic and diabetic retinopathy and genetic susceptibility was analyzed. The SNP analysis was performed by sequenommassarray genotyping and the Hardy-Weinberg balance test was performed on the control group by the exacttest method. The clinical indexes of diabetic retinopathy and diabetic retinopathy were analyzed by the method of variance analysis. The difference in the mean value of the different genotypes at different loci. The unconditional logistics regression method calculated the relative dominance of the risk alleles compared to the confidence intervals of oddsratios and 95%, and measured the correlation between these alleles and diabetic retinopathy. The haploview and snpstats analysis were located on the same gene. The linkage degree and haplotype effect at the dry site. All the statistical tests were bilateral probability tests and test level p=0.05. results: the frequency distribution of insulin therapy in the Dr group and the NDR group was statistically different with the Pearson 's chi square test; Welch' st assay was used to analyze age, durationofdiabetes, Totalcholesterol, The mean values of triglycerides, LDL, GFR, and CP were statistically different between the Dr group and the NDR group. The relationship between the SNP and the diabetes clinical indicators was analyzed by variance analysis. It was found that the mean value of glycosylated hemoglobin under the different genotype of kiaa0825rs17376456 and igf1rs6214 loci was statistically different. In lekr1-ccnl1rs13064954 and arhga. The mean value of glycerol three in the different genotypes of the p22rs4838605 loci was statistically different. In the analysis of diabetic retinopathy, the mthfrrs1537516 locus had a significant difference in the mean value of glycerol three fat under different genotypes. The mean value of TG in the mutant genotype was significantly higher than that in the wild type. Also, the MTHFR base was found. The rs1537516 locus affects the insulin level in patients with diabetic retinopathy. This study also found that the mean value of Cys-C under the different genotypes of the nos3rs3918227 and ulekr1-ccnl1rs13064954 loci was statistically different. Under the allele model, the lekr1-ccnl1rs13064954 locus was transformed from the G allele to the A allele. The risk of disease retinopathy is 43% lower than that of diabetic retinopathy (or=0.57,95%ci:0.34-0.96, p=0.032). The effect of genetic polymorphism on the genetic susceptibility to diabetic retinopathy under different genetic models by logistic regression analysis. After correction by age and sex, log-additive model, IGS F21-klhdc7ars3007729 loci, individuals carrying t alleles increased the risk of diabetes by 26% (or=1.26,95%ci:1.01-1.56, p=0.037) than those with C alleles, and under the co dominant model, the risk of individuals carrying nos3rs1799983gt genotypes increased by 49% than those with GG based individuals (or=1.49). 95%ci:1.02-2.18, p=0.002), the risk of carrying the nos3rs3918227ca genotype was 1.41 times the risk of diabetes in individuals with CC genotype (or=1.41,95%ci:0.91-2.20, p=0.046), and the risk of diabetes with the arhgap22rs4838605tc genotype was 1.54 times as high as that of a TT genotype (or=1.54,95%ci:1.06-2.24, P=0.003) the effects of genetic polymorphisms on the genetic susceptibility to diabetic retinopathy under different genetic models were analyzed by logistic regression. It was found that under the co dominant model, the risk of individuals carrying the igsf21-klhdc7ars3007729tt genotype was a diabetic retinopathy with CC genotype under the co dominant model without any correction. The risk of disease was 2.11 times (or=2.11,95%ci:1.26-3.53, p=0.013); in the log-additive model, the risk of diabetic retinopathy decreased by 42% (or=0.58,95%ci:0.34-0.96, p=0.034) when the allele of the lekr1-ccnl1rs13064954 site was transformed from G to a: NOS3 gene rs1799983 and rs3918227 and ARHGAP22 polymorphisms Diabetes related; (1) LEKR1-CCNL1 rs13064954 gene polymorphism is associated with diabetic retinopathy; (2) IGSF21-KLHDC7A rs3007729 polymorphism is associated with diabetic retinopathy and diabetic retinopathy; (3) KIAA0825 rs17376456 and IGF1 rs6214 gene polymorphisms and diabetic patients glycosylated blood red Protein correlation; LEKR1-CCNL1 rs13064954 and ARHGAP22rs4838605 gene polymorphisms are associated with triglyceride levels in diabetic patients. (4) the MTHFR rs1537516 locus is associated with the levels of glycerol three and insulin in patients with diabetic retinopathy.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R587.2;R774.1

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3 記者 宋哲民 夏景珉;結(jié)合臨床開展基因多態(tài)性研究實現(xiàn)疾病診斷與治療的個體化[N];中國中醫(yī)藥報;2000年

4 記者 馮立中　通訊員 朱沛炎;基因多態(tài)性或增糖尿病發(fā)病風(fēng)險[N];健康報;2011年

5 通訊員　段文利;我國學(xué)者發(fā)現(xiàn)全身感染的高危基因[N];光明日報;2003年

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7 藺曉慧;糖尿病視網(wǎng)膜病變臨床指標及基因多態(tài)性的研究[D];重慶醫(yī)科大學(xué);2016年

8 郭妍妍;1、蒙，漢族TIM1基因多態(tài)性和IL13表達與PNS的相關(guān)性研究 2、蒙，漢族TIM3基因多態(tài)性和IFN-γ表達與PNS的相關(guān)性研究[D];南方醫(yī)科大學(xué);2016年

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10 王東;煤礦工人輪班制與RAAS基因多態(tài)性交互作用對EH的影響[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2012年

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