血浆同型半胱氨酸、瘦素水平及相关基因多态性与妊娠期糖尿病的关联性研究

发布时间：2018-01-21 15:36

本文关键词： 妊娠期糖尿病同型半胱氨酸瘦素基因多态性　出处：《华中科技大学》2016年博士论文　论文类型：学位论文

【摘要】：目的：1.了解妊娠期糖尿病(gestational diabetes mellitus,GDM)发生的相关危险因素,并分析各因素的危险程度：2.探讨血浆同型半胱氨酸水平(total homocysteine,tHcy)、相关代谢基因单核苷酸多态性(MTHFR C677、MTHFR A1298C、MTR A2756G和MTRRA66G)及基因-环境交互作用与GDM易感性的关系；3.探讨血浆瘦素水平、LEP G2548A、LEPR Gln223Arg多态性及基因-环境交互作用与GDM易感性的关系。方法：1.第一部分采用1：1配对病例对照研究,对372对GDM孕妇和正常孕妇进行了GDM相关危险因素的流行病学调查,利用因子分析探讨研究对象的膳食模式,采用配对t/x2检验、单因素及多因素条件Logistic回归筛选出GDM的主要危险因素,并计算比值比(Odd ratio, OR)和95%可信区间(confidence interval,CI)。2.以第一部分中采样前3个月内未服用叶酸的363名汉族孕妇(166名GDM和197名对照)作为第二部分研究对象,采集其空腹静脉血5m1,采用高效液相色谱-荧光检测法测定血浆tHcy水平、TaqMan基因分型技术对MTHFR C677T、MTHFR A1298C、MTR A2756G和MTRR A66G位点进行基因分型,分析血浆tHcy水平及代谢相关基因多态性与GDM易感性的关联。随后,利用基于2×4叉生分析表的相加和相乘模型分析基因多态性与环境危险因素之间可能存在的交互作用对GDM易感性的影响。3.以第一部分中的696名汉族孕妇(350名GDM和346名对照)作为第三部分研究对象,采集其空腹静脉血5m1,采用酶联免疫吸附实验测定血浆瘦素水平,TaqMan基因分型技术对LEP G2548A和LEPR Gln223Arg位点进行基因分型,分析血浆瘦素水平、LEP G2548A、LEPR Gln223Arg多态性与GDM易感性的关联。随后,利用基于2×4叉生分析表的相加和相乘模型分析基因多态性与环境危险因素之间可能存在的交互作用对GDM易感性的影响。结果：1.研究发现孕妇年龄大(OR=1.14,95%CI:1.09-1.20)、孕前BMI值高(OR=1.10, 95%CI:1.02-1.17)、一级亲属患有T2DM(OR=4.12,95%CI:2.03-8.34)、有GDM史(OR=9.39,95%CI:1.48-59.72)、孕早期服用孕激素(OR=1.63,95%CI:1.11-2.40)、居住地1公里内有工厂(OR=1.69,95%CI:1.13-2.55)、久坐(OR=1.52,95%CI: 1.04-2.22)和“奶蛋水果模式”膳食负荷高(OR=1.47,95%CI:1.15-1.89)是GDM的危险因素,而孕早期及孕前叶酸服用时间长(OR=0.64,95%CI:0.47-0.86)、居住地距离公路远(OR=0.64,95%CI:0.49-0.84)、平均每周运动天数多(OR-0.78,95%CI: 0.66-0.93),工作日工作时间长(OR=0.73,95%CI:0.55-0.96)和“绿色蔬菜模式”膳食负荷高(OR=0.75,95%CI:0.59-0.95)是GDM的保护因素。2.血浆tHcy水平、代谢相关基因多态性及基因-环境交互作用与GDM2.1 GDM组孕妇血浆tHcy水平明显高于对照组(6.96±1.30 vs.6.42±1.28μmol/L, P=0.005),且血浆tHcy水平与胰岛素抵抗指数(homeostasis model of insulin resistance. HOMA-IR)正相关(rs=0.08,P=0.02),与胰岛p细胞功能指数(homeostasis model of beta cell function, HOMA-f)负相关(rs=-0.14,P=0.01)。2.2携带MTHFR C677T位点T等位基因的孕妇较未携带者GDM发生风险降低(OR=0.65,95%CI:0.48-0.90)c未发现MTFHR A1298C, MTR A2756G、MTRRA66G与GDM易感性相关。2.3 MTHFR C677T多态性与“孕早期服用孕激素”、“孕前至孕早期叶酸服用时长”之间存在正相加交互作用。MTHFR A1298C多态性与“孕前至孕早期叶酸服用时长”之间存在正相加交互作用。3.血浆瘦素水平、LEP G2548A、LEPR Gln223Arg多态性及基因-环境交互作用与GDM3.1 GDM组孕妇血浆瘦素水平与对照组无统计学差异(27.35±2.56 vs.26.73± 2.13μg/L, P=0.33);但是单纯空腹血糖受损组(35.40±2.02μg/L)和空腹血糖/糖耐量均受损组(33.41±3.17μg/L)孕妇血浆瘦素水平均明显高于对照组(P0.05)：且血浆瘦素水平与HOMA-IR正相关(rs=0.43,P0.001),与HOMA-f负相关(rs=-0.09,P=0.02)。3.2携带LEP G2548A位点G等位基因的个体发生GDM的风险是非携带者的1.29倍(OR=1.29,95%CI：1.01-1.64)。未发现LEPR Gln223Arg与GDM易感性相关。3.3 LEP G2548A多态性与孕前BMI、“奶蛋水果模式”存在正相加交互作用。LEPR Gln223Arg多态性与孕前BMI、久坐、“奶蛋水果模式”存在正相加交互作用。结论：1.GDM孕妇较正常孕妇血浆tHcy水平升高,MTHFR C677T位点CT遗传变异可能与GDM发病风险降低相关。2.血浆瘦素水平升高与GDM存在相关性,携带LEP G2548A位点G等位基因可能与GDM发病风险增加相关。3. MTHFR C677T/A1298C多态性与“孕前至孕早期叶酸服用时长”,LEP G2548A/ LEPR Gln223Arg多态性与孕前BMI、“奶蛋水果模式”之间存在正相加交互作用；MTHFR C677T多态性与“孕早期服用孕激素”,LEPR Gln223Arg多态性与久坐之间也存在正相加交互作用：未发现各位点与GDM相关危险因素之间存在相乘交互作用。创新点：本研究首次探讨了中国汉族人群Hcy代谢相关基因和瘦素基因多态性与GDM易感性之间的关联,填补了国内外相关研究领域的一个空白。从环境、基因及两者交互作用多个角度,识别和评估了GDM的危险因素及危险程度,为GDM预防措施的提出提供了参考依据。
[Abstract]:Objective: to understand the 1. gestational diabetes mellitus (gestational diabetes, mellitus, GDM) the relevant risk factors, and to analyze the risk degree of each factor: 2. to investigate the levels of plasma homocysteine (total homocysteine, tHcy), metabolism related gene single nucleotide polymorphism (MTHFR C677, MTHFR A1298C, MTR A2756G and MTRRA66G) and the relationship between gene the interaction between environment and susceptibility to GDM; 3. to investigate the plasma leptin level, LEP G2548A, the relationship between LEPR Gln223Arg polymorphism and gene environment interaction and susceptibility to GDM. Methods: 1. the first part using 1:1 matched case-control study, the epidemiological investigation of GDM related risk factors of 372 GDM pregnant women and normal pregnant women. Analysis of the study of dietary patterns using factor, using paired t/x2 test, screening out the main risk factors of GDM univariate and multivariate conditional Logistic regression, And calculate the odds ratio (Odd ratio, OR) and 95% confidence intervals (confidence interval, CI.2.) in the first part before sampling 363 Han pregnant women not taking folic acid within 3 months (166 GDM and 197 controls) as the second part of the study, collected fasting blood 5m1, plasma tHcy by using high performance liquid chromatography with fluorescence detection and TaqMan genotyping of MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genotyping, correlation analysis of tHcy level and metabolism related gene polymorphism with the susceptibility of GDM plasma. Then, based on the interaction between 2 * 4 crossover analysis table of additive and multiplicative model analysis of gene polymorphism and environmental risk factors on GDM susceptibility of.3. to 696 Han pregnant women in the first part (350 GDM and 346 controls) as the third part of the research object, collecting the air Abdominal venous blood 5m1, plasma leptin levels were determined by enzyme linked immunosorbent assay, TaqMan genotyping of LEP G2548A and LEPR Gln223Arg genotyping and analysis of plasma levels of leptin, LEP G2548A, Gln223Arg Association of LEPR polymorphism and GDM susceptibility. Then, based on the interaction between 2 * 4 crossover analysis table of additive and multiplicative model analysis of gene polymorphism and environmental risk factors in susceptibility to GDM. Results: 1. study found that maternal age (OR=1.14,95%CI:1.09-1.20), pre high values of BMI (OR=1.10, 95%CI:1.02-1.17), first-degree relatives with T2DM (OR=4.12,95%CI:2.03-8.34), GDM (OR=9.39,95%CI:1.48-59.72), the history of the first trimester progesterone (OR=1.63,95%CI:1.11-2.40), live within 1 miles of the factory (OR=1.69,95%CI:1.13-2.55), sedentary (OR=1.52,95%CI: 1.04-2.22) and "milk egg fruit pattern" Dietary high load (OR=1.47,95%CI:1.15-1.89) is a risk factor for GDM, and early pregnancy and pre pregnancy folic acid (OR=0.64,95%CI:0.47-0.86), the residence time is long distance highway far (OR=0.64,95%CI:0.49-0.84), the average number of days a week (OR-0.78,95%CI: 0.66-0.93), many working days long working time (OR=0.73,95%CI:0.55-0.96) and "green vegetables" dietary high load (OR=0.75,95%CI:0.59-0.95) is the level of plasma.2. tHcy GDM protective factors, polymorphism of metabolism related genes and gene environment interaction with the GDM2.1 GDM group in maternal plasma tHcy levels were significantly higher than those in the control group (6.96 + 1.30 vs.6.42 + 1.28 mol/L, P=0.005), and plasma tHcy levels and insulin resistance index (homeostasis model of insulin resistance. (HOMA-IR) positive correlation rs=0.08, P=0.02), and the index of islet P cell function (homeostasis model of beta cell function, HOMA-f) negative Related (rs=-0.14, P=0.01).2.2 MTHFR C677T carrying T allele of pregnant women than non carriers GDM risk reduction (OR=0.65,95%CI:0.48-0.90) of C MTFHR was not found in A1298C, MTR A2756G, MTRRA66G.2.3 MTHFR C677T associated with GDM susceptibility polymorphism and early pregnancy by taking progesterone "," pre pregnancy in early pregnancy to take folic acid long "was a significant interaction between.MTHFR A1298C polymorphism and" pre pregnancy to early pregnancy folic acid time between positive additive interaction in.3. plasma levels of leptin, LEP G2548A, LEPR Gln223Arg polymorphism and gene environment interaction with the GDM3.1 GDM group in maternal plasma leptin levels and the control group showed no significant difference (27.35 + 2.56 vs.26.73 + 2.13 g/L, P=0.33); but the impaired fasting glucose group (35.40 + 2.02 u g/L) and fasting blood glucose / glucose tolerance was impaired group (33.41 + 3.17 u g/L) maternal plasma leptin In the water were significantly higher than control group (P0.05), and plasma leptin levels were positively correlated with HOMA-IR (rs=0.43, P0.001), and negatively correlated with HOMA-f (rs=-0.09, P=0.02).3.2 LEP G2548A G sites carrying the risk allele GDM was 1.29 times higher than non carriers (OR= 1.29,95%CI:1.01-1.64) LEPR Gln223Arg. With the development of GDM.3.3 LEP G2548A polymorphism and pre pregnancy BMI found "milk and eggs fruit mode" are additive interaction.LEPR Gln223Arg polymorphism and BMI before pregnancy, sedentary, milk egg fruit model has positive additive interaction. Conclusion: pregnant women with 1.GDM compared with normal plasma levels of tHcy in pregnant women, MTHFR CT genetic locus C677T variation and GDM may reduce the risk of elevated.2. plasma leptin levels related correlation with the existence of GDM, with LEP G2548A G allele may increase the risk associated with the onset of GDM.3. MTHFR C677T/A1298C Polymorphism and "pre pregnancy to early pregnancy folic acid long, LEP G2548A/ LEPR Gln223Arg polymorphism and BMI before pregnancy, there was a significant interaction between milk and egg fruit mode"; MTHFR C677T polymorphism and early pregnancy progestin ", there was a significant interaction between LEPR Gln223Arg polymorphism and sedentary: that you and GDM related risk factors are multiplicative interaction between. Innovation: This is the first time to explore the relationship between leptin and Hcy metabolism related genes Chinese genetic polymorphism and susceptibility to GDM, to fill a gap in the relevant research fields at home and abroad. From the aspects of environment, and the interaction between the two genes, to identify and assess the risk factors of GDM and the degree of risk, provide a reference for the proposed GDM preventive measures.

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R714.256

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