本文關(guān)鍵詞： 妊娠期糖尿病 同型半胱氨酸 瘦素 基因多態(tài)性　出處：《華中科技大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：目的：1.了解妊娠期糖尿病(gestational diabetes mellitus,GDM)發(fā)生的相關(guān)危險因素,并分析各因素的危險程度：2.探討血漿同型半胱氨酸水平(total homocysteine,tHcy)、相關(guān)代謝基因單核苷酸多態(tài)性(MTHFR C677、MTHFR A1298C、MTR A2756G和MTRRA66G)及基因-環(huán)境交互作用與GDM易感性的關(guān)系；3.探討血漿瘦素水平、LEP G2548A、LEPR Gln223Arg多態(tài)性及基因-環(huán)境交互作用與GDM易感性的關(guān)系。方法：1.第一部分采用1：1配對病例對照研究,對372對GDM孕婦和正常孕婦進行了GDM相關(guān)危險因素的流行病學(xué)調(diào)查,利用因子分析探討研究對象的膳食模式,采用配對t/x2檢驗、單因素及多因素條件Logistic回歸篩選出GDM的主要危險因素,并計算比值比(Odd ratio, OR)和95%可信區(qū)間(confidence interval,CI)。2.以第一部分中采樣前3個月內(nèi)未服用葉酸的363名漢族孕婦(166名GDM和197名對照)作為第二部分研究對象,采集其空腹靜脈血5m1,采用高效液相色譜-熒光檢測法測定血漿tHcy水平、TaqMan基因分型技術(shù)對MTHFR C677T、MTHFR A1298C、MTR A2756G和MTRR A66G位點進行基因分型,分析血漿tHcy水平及代謝相關(guān)基因多態(tài)性與GDM易感性的關(guān)聯(lián)。隨后,利用基于2×4叉生分析表的相加和相乘模型分析基因多態(tài)性與環(huán)境危險因素之間可能存在的交互作用對GDM易感性的影響。3.以第一部分中的696名漢族孕婦(350名GDM和346名對照)作為第三部分研究對象,采集其空腹靜脈血5m1,采用酶聯(lián)免疫吸附實驗測定血漿瘦素水平,TaqMan基因分型技術(shù)對LEP G2548A和LEPR Gln223Arg位點進行基因分型,分析血漿瘦素水平、LEP G2548A、LEPR Gln223Arg多態(tài)性與GDM易感性的關(guān)聯(lián)。隨后,利用基于2×4叉生分析表的相加和相乘模型分析基因多態(tài)性與環(huán)境危險因素之間可能存在的交互作用對GDM易感性的影響。結(jié)果：1.研究發(fā)現(xiàn)孕婦年齡大(OR=1.14,95%CI:1.09-1.20)、孕前BMI值高(OR=1.10, 95%CI:1.02-1.17)、一級親屬患有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公里內(nèi)有工廠(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”膳食負荷高(OR=1.47,95%CI:1.15-1.89)是GDM的危險因素,而孕早期及孕前葉酸服用時間長(OR=0.64,95%CI:0.47-0.86)、居住地距離公路遠(OR=0.64,95%CI:0.49-0.84)、平均每周運動天數(shù)多(OR-0.78,95%CI: 0.66-0.93),工作日工作時間長(OR=0.73,95%CI:0.55-0.96)和“綠色蔬菜模式”膳食負荷高(OR=0.75,95%CI:0.59-0.95)是GDM的保護因素。2.血漿tHcy水平、代謝相關(guān)基因多態(tài)性及基因-環(huán)境交互作用與GDM2.1 GDM組孕婦血漿tHcy水平明顯高于對照組(6.96±1.30 vs.6.42±1.28μmol/L, P=0.005),且血漿tHcy水平與胰島素抵抗指數(shù)(homeostasis model of insulin resistance. HOMA-IR)正相關(guān)(rs=0.08,P=0.02),與胰島p細胞功能指數(shù)(homeostasis model of beta cell function, HOMA-f)負相關(guān)(rs=-0.14,P=0.01)。2.2攜帶MTHFR C677T位點T等位基因的孕婦較未攜帶者GDM發(fā)生風(fēng)險降低(OR=0.65,95%CI:0.48-0.90)c未發(fā)現(xiàn)MTFHR A1298C, MTR A2756G、MTRRA66G與GDM易感性相關(guān)。2.3 MTHFR C677T多態(tài)性與“孕早期服用孕激素”、“孕前至孕早期葉酸服用時長”之間存在正相加交互作用。MTHFR A1298C多態(tài)性與“孕前至孕早期葉酸服用時長”之間存在正相加交互作用。3.血漿瘦素水平、LEP G2548A、LEPR Gln223Arg多態(tài)性及基因-環(huán)境交互作用與GDM3.1 GDM組孕婦血漿瘦素水平與對照組無統(tǒng)計學(xué)差異(27.35±2.56 vs.26.73± 2.13μg/L, P=0.33);但是單純空腹血糖受損組(35.40±2.02μg/L)和空腹血糖/糖耐量均受損組(33.41±3.17μg/L)孕婦血漿瘦素水平均明顯高于對照組(P0.05)：且血漿瘦素水平與HOMA-IR正相關(guān)(rs=0.43,P0.001),與HOMA-f負相關(guān)(rs=-0.09,P=0.02)。3.2攜帶LEP G2548A位點G等位基因的個體發(fā)生GDM的風(fēng)險是非攜帶者的1.29倍(OR=1.29,95%CI：1.01-1.64)。未發(fā)現(xiàn)LEPR Gln223Arg與GDM易感性相關(guān)。3.3 LEP G2548A多態(tài)性與孕前BMI、“奶蛋水果模式”存在正相加交互作用。LEPR Gln223Arg多態(tài)性與孕前BMI、久坐、“奶蛋水果模式”存在正相加交互作用。結(jié)論：1.GDM孕婦較正常孕婦血漿tHcy水平升高,MTHFR C677T位點CT遺傳變異可能與GDM發(fā)病風(fēng)險降低相關(guān)。2.血漿瘦素水平升高與GDM存在相關(guān)性,攜帶LEP G2548A位點G等位基因可能與GDM發(fā)病風(fēng)險增加相關(guān)。3. MTHFR C677T/A1298C多態(tài)性與“孕前至孕早期葉酸服用時長”,LEP G2548A/ LEPR Gln223Arg多態(tài)性與孕前BMI、“奶蛋水果模式”之間存在正相加交互作用；MTHFR C677T多態(tài)性與“孕早期服用孕激素”,LEPR Gln223Arg多態(tài)性與久坐之間也存在正相加交互作用：未發(fā)現(xiàn)各位點與GDM相關(guān)危險因素之間存在相乘交互作用。創(chuàng)新點：本研究首次探討了中國漢族人群Hcy代謝相關(guān)基因和瘦素基因多態(tài)性與GDM易感性之間的關(guān)聯(lián),填補了國內(nèi)外相關(guān)研究領(lǐng)域的一個空白。從環(huán)境、基因及兩者交互作用多個角度,識別和評估了GDM的危險因素及危險程度,為GDM預(yù)防措施的提出提供了參考依據(jù)。
[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.

【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R714.256

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