糖尿病视网膜病变临床指标及基因多态性的研究

发布时间：2018-07-06 07:05

本文选题：糖尿病 + 糖尿病视网膜病变　；参考：《重庆医科大学》2016年博士论文

【摘要】：目的:糖尿病视网膜病变(diabetic retinopathy,DR)是一种较常见的糖尿病微血管并发症之一,糖尿病病程、血糖水平、血压、血脂等临床因素对糖尿病视网膜病变的发生发展有一定的影响。但糖尿病视网膜病变在发病的病程、严重程度上却存在很大的个体差异,这种差异性被认为是由于基因多态性造成的。本研究的目的是从临床指标及基因多态性两方面研究分析影响糖尿病视网膜病变发生发展的相关因素。材料方法:自2014年6月1日至2015年6月31日,参照相关诊断标准,在内蒙古自治区人民医院内分泌科住院患者中收集糖尿病患者319例,同期在内蒙古自治区人民医院体检中心收集正常人群对照387例。根据眼底荧光造影将糖尿病患者分为糖尿病不伴随视网膜病变(NDR组)和糖尿病视网膜病变(DR组),DR组患者175例,NDR组患者144例。收集患者的样本信息包括:一般信息:姓名、性别、年龄、民族、住院号、身份证号、身高、体重、体重指数;临床信息:糖尿病病程、既往病史、吸烟饮酒史、降糖药和胰岛素使用情况、有否糖尿病视网膜病变;生化指标:空腹血糖、糖化血红蛋白、总胆固醇、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、肾小球滤过率、空腹C肽、胱抑素C。并以住院号或编号对应样本进行了数据资料整理。2.采用Pearson’s卡方检验分析分类变量的频率分布在DR和NDR组间是否存在统计学差异,利用Welch’s t检验分析临床指标(Duration ofdiabetes、bmi、fastingglucose、hba1c、totalcholesterol、triglycerides、ldlcholesterol、hdlcholesterol、gfr、cp、urea、cr、cys-c、ins)的均值在dr组和ndr组间是否存在统计学差异。选取23个单核苷酸多态性位点进行了糖尿病及糖尿病视网膜病变与遗传易感性关联分析研究。使用sequenommassarray基因分型技术进行snp分析,利用exacttest方法对对照组进行hardy-weinberg平衡检验;采用方差分析的方法分析糖尿病及糖尿病视网膜病变临床指标的均值在不同位点的不同基因型下的差异。无条件logistics回归方法计算风险等位基因的相对优势比oddsratios和95%的置信区间,衡量这些突变等位基因与糖尿病及糖尿病视网膜病变的相关性。利用haploview和snpstats分析位于同一个基因上若干个位点的连锁程度及单体型效应。所有统计检验均为双侧概率检验,检验水准p=0.05。结果:采用pearson’s卡方检验分析发现胰岛素治疗在病例dr组和ndr组间的频数分布存在统计学差异;welch’st检验分析年龄、durationofdiabetes、totalcholesterol、triglycerides、ldl、gfr、cp的均值在dr组和ndr组间存在统计学差异。采用方差分析的方法分析snp与糖尿病临床指标之间的关系,发现在kiaa0825rs17376456和igf1rs6214位点的不同基因型下糖化血红蛋白的均值存在统计学差异。在lekr1-ccnl1rs13064954和arhgap22rs4838605位点的不同基因型下甘油三脂的均值存在统计学差异。在糖尿病视网膜病变的分析结果发现,mthfrrs1537516位点影响甘油三脂在不同基因型下的均值存在统计学差异,突变基因型的tg的均值显著高于野生型的均值。还发现mthfr基因rs1537516位点影响糖尿病视网膜病变患者的胰岛素水平;本研究还发现nos3rs3918227位点和ulekr1-ccnl1rs13064954位点的不同基因型下cys-c的均值存在统计学差异。在等位基因模型下,lekr1-ccnl1rs13064954位点由g等位基因突变成a等位基因时,糖尿病视网膜病变的患病风险较糖尿病不伴随视网膜病变的风险降低了43%(or=0.57,95%ci:0.34-0.96,p=0.032)。采用逻辑回归分析不同遗传模型下,基因多态性对糖尿病视网膜病变遗传易感性的影响。在经过年龄和性别的校正后,log-additive模型下,igsf21-klhdc7ars3007729位点,携带t等位基因的个体较携带c等位基因个体糖尿病的发病风险增加了26%(or=1.26,95%ci:1.01-1.56,p=0.037);在共显性模型下,携带nos3rs1799983gt基因型的个体的发病风险较携带gg基因型个体的糖尿病患病风险增加了49%(or=1.49,95%ci:1.02-2.18,p=0.002),携带nos3rs3918227ca基因型的个体的发病风险是携带cc基因型个体的糖尿病患病风险的1.41倍(or=1.41,95%ci:0.91-2.20,p=0.046),携带arhgap22rs4838605tc基因型的个体的糖尿病患病风险是携带tt基因型个体1.54倍(or=1.54,95%ci:1.06-2.24,p=0.003)采用逻辑回归分析不同遗传模型下,基因多态性对糖尿病视网膜病变遗传易感性的影响。发现在没有做任何修正时,在共显性模型下,携带igsf21-klhdc7ars3007729tt基因型的个体的发病风险是携带cc基因型个体的糖尿病视网膜病变患病风险的2.11倍(or=2.11,95%ci:1.26-3.53,p=0.013);在log-additive模型下,lekr1-ccnl1rs13064954位点的等位基因由g突变成a时,糖尿病视网膜病变的患病风险降低了42%(or=0.58,95%ci:0.34-0.96,p=0.034)结论:NOS3基因rs1799983和rs3918227和ARHGAP22 rs4838605基因多态性与糖尿病相关;(1)LEKR1-CCNL1 rs13064954基因多态性与糖尿病患者的糖尿病视网膜病变相关;(2)IGSF21-KLHDC7A rs3007729基因多态性与糖尿病和糖尿病患者的糖尿病视网膜病变相关;(3)KIAA0825 rs17376456和IGF1 rs6214基因多态性与糖尿病患者的糖化血红蛋白相关;LEKR1-CCNL1 rs13064954和ARHGAP22rs4838605基因多态性与糖尿病患者的甘油三酯水平相关。(4)MTHFR rs1537516位点与糖尿病视网膜病变患者的甘油三脂和胰岛素水平均相关。
[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.
【学位授予单位】：重庆医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R587.2;R774.1

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