环境与基因的交互作用对早期自然流产的影响

发布时间：2019-05-24 17:06

【摘要】：目的：早期自然流产(early miscarriage, EM)虽经大量研究,由于病因复杂,机制不清,缺乏预防及早期诊断、早期治疗的方法。随着对基因功能研究的深入,基因和环境与疾病的关联已经成为疾病研究的新策略。目前关于EM的研究较为局限,虽已知自身免疫紊乱在EM发病过程中具有重要作用,但其发生发展过程中环境因素的致病风险、环境与基因交互作用的影响及其与机体自身免疫紊乱的关系研究报道较少。为此采用流行病学调查、环境与基因交互作用分析、免疫调节细胞检测等研究方法,探讨环境、基因、免疫等因素对EM的影响及其相互关联,为阐明EM的危险因素、发病机制、早期预防和治疗等提供相关科学依据。研究方法： 1流行病学调查：应用基于医院调查的病例对照研究方法,采用问卷调查方式,调查郑州市三家省市级医院640例妊娠早期流产患者和1280例中晚期正常围产保健妊娠妇女生活环境情况,分析环境因素对妊娠、流产的影响。 2基因多态性及交互作用分析：对所有调查对象提取全基因组DNA,分析抑制性免疫调节基因Foxp3基因的两个位点rs3761548、rs5953280和CTLA-4基因的2个位点rs231775和rs5742909的多态性,采用统计软件SPSS21.0拟合Logistic和MDR软件分析基因-基因、基因-环境的交互作用对流产的影响。 3血清PAEs及Treg检测：以从事服装销售的女性EM患者65例和正常妊娠者49例、非销售职业的EM患者65例和正常妊娠者70例为研究对象,采用流式细胞仪检测外周血及流产胚胎蜕膜组织中调节性T淋巴细胞(Treg)的分布变化,采用高效液相色谱法检测血清中邻苯二甲酸酯类(PAEs)中邻苯二甲酸二乙酯(DEP)、邻苯二甲酸二丁酯(DBP)、苯二甲酸二异辛酯(DEHP)水平,初步探讨环境污染物和Treg数量变化与EM的关系。结果： 1销售职业、自然流产史、主动流产史、熬夜、夜班可能是早期流产的风险因子：单因素Logistic回归分析结果显示,从事销售(OR=2.417,95%CI=1.384～2.918)和财务职业(OR=1.632,95%CI=1.113～2.272)的女性易于自然流产；既往的自然流产史(OR=2.583,95%CI=1.197～4.069)和主动流产史(OR=1.872.95%CI=1.066～2.849)是妊娠早期流产的危险因素；经常值夜班(OR=1.473.95%CI=1.113～1.842)和经常熬夜(OR=1.464.95%CI=1.072～2.820)是妊娠早期流产的危险因素；孕前紧张(OR=1.345,95%CI=1.013～1.626)和工作压力过大(OR=1.462,95%CI=1.172～1.716)也是流产的危险因素；而妊娠前补充复合维生素(OR=0.761,95%CI=0.485～0.923)和适当体育锻炼(OR=0.735.95%CI=0.512～0.913)是妊娠早期流产的保护性因素。经多因素分析后,销售职业(OR=2.417)、自然流产史(OR=3.166)、主动流产史(OR=2.396)、夜班(OR=1.473)、熬夜(OR=1.464)等5种因素显著增加了流产的风险；而体育锻炼(OR=0.735)、补充复合维生素(OR=0.761)则是流产的保护性因素。 2Foxp3基因rs3761548的风险等位基因C在病例组与对照组的分布差异有统计学意义(χ2=4.927,P=0.012)。突变纯合子CC在流产组中显著高于对照组(χ2=6.387,P=0.011),以及隐性遗传模型能增加疾病的风险(OR=1.275,95%CI=1.012～1.417), Foxp3的rs5953280位点与妊娠早期流产无明显关联。CTLA-4的2个位点rs5742909. rs231775与妊娠早期流产无明显关联。 3用Logistic回归模型分析两两位点间交互作用,调整了职业、自然流产史、主动流产史、夜班、熬夜、体育锻炼、补充复合维生素等因素后,结果显示四位点间均未见交互作用。用Logistic回归模型分析四位点与环境风险因子进行一阶交互作用,也未发现明显的交互效应。当采用多因子降维法(multifactor dimensionality reduction, MDR)进行高阶交互分析时,发现最佳的交互模型是自然流产史、夜班、熬夜、rs3761548的四因子交互模型,该模型的检验平衡集精度为0.62,交叉验证率为90%,模型P值为0.01。 4服装销售病例组血清DBP水平[0.454±0.386(μg/ml)]高于非销售对照组血清DBP水平[0.216±0.155(μg/ml)],差异有统计学意义(这=0.001);服装销售病例组外周血及蜕膜组织中Treg[(0.937±0.212)%,(1.136±0.428)%)]显著低于非销售对照组[(1.327±0.438)%,(2.115±0.498)%)],差异有统计学意义(两组P=0.000)。服装销售组的血清DBP水平与其外周血Treg数量负相关(P0.05)。结论： 1在中国汉族育龄期女性人群中,从事销售职业、有自然流产史、主动流产史、夜班工作和经常熬夜能显著增加妊娠早期自然流产的风险；而孕前补充复合维生素、适当的体育锻炼则可以降低自然流产的风险。 2Foxp3基因的rs3761548位点可增加中国汉族育龄期女性妊娠早期自然流产的风险；而且自然流产史、夜班、熬夜以及rs3761548位点四因素之间存在交互效应,能增加流产风险。 3服装销售女性血清DBP水平高于非销售女性,可能影响外周血Treg数量；早期自然流产可能与母胎界面组织内Treg数量减少有关,而与外周血Treg数量无显著性关系。
[Abstract]:Purpose: Early-stage spontaneous abortion (EM) is a lot of research, because of the complicated causes, unclear mechanism, lack of prevention and early diagnosis, and early treatment With the study of gene function, the association of gene and environment with disease has become a new way of disease research. At present, the research on EM is limited, although it is known that the autoimmune disorder has an important role in the process of EM, the risk of the environmental factors in the course of development, the influence of the environment and the interaction of the gene and the relationship with the immune disorder of the body are reported. The effects of environment, gene, immunity and other factors on EM and their correlation are discussed in this paper. The risk factors and the pathogenesis of EM are discussed. To provide relevant scientific basis, such as system, early prevention and treatment, etc. According to. Research Methods:1. Epidemiological survey: A case-control study based on hospital investigation was used to investigate 640 cases of early abortion and 1280 cases of normal perinatal health-care pregnant women in three provincial hospitals in Zhengzhou. the condition of living environment is analyzed, the environmental factors are analyzed for pregnancy, Effects of abortion on 2 loci, rs3761548, rs5953280 and CTLA-4, and rs231775 and rs5742 of the two loci, rs3761548, rs5953280, and CTLA-4, were extracted from all the investigated subjects. The polymorphism of 909 was analyzed by using the statistical software SPSS21.0, and the interaction of the gene, gene, gene and environment was analyzed by means of the logistic and MDR software. Effect of use on abortion. Serum PAEs and Treg detection:65 cases of female EM and 49 normal pregnant women,65 cases of non-marketing and normal pregnancy. The distribution of regulatory T-lymphocytes (Treg) in the decidua tissues of peripheral blood and abortion was detected by flow cytometry, and the diethyl phthalate (DEP) and o-phthalonitrile in the serum were detected by high performance liquid chromatography. The level of dibutyl phthalate (DBP) and dioctyl phthalate (DEHP), and the number of environmental pollutants and Treg was discussed. change of quantity Results:1. The history of spontaneous abortion, the history of active abortion, the late night and the night shift may be the risk factors of early abortion. The results of univariate logistic regression analysis show that the sales (OR = 2.417,95% CI = 1.384-2.918) and the financial profession (OR = 1.632,95% CI = 1.113 ~ 2). The history of spontaneous abortion (OR = 2.583,95% CI = 1.197-4.069) and the history of active abortion (OR = 1.872.95% CI = 1.066-2.849) were the risk factors for early abortion in the early stage of pregnancy; the frequent night shift (OR = 1.473.95% CI = 1.113-1.842) and the frequent stay-up (OR = 1.464.95% CI = 1.072-2.820) were the risk factors for early abortion in the pregnancy; pre-pregnancy stress (OR = 1.345,95% CI = 1.013-1.626) and excessive working pressure (OR = 1.462,95% CI = 1.172-1). 716) is also the risk factor for abortion; and the pre-pregnancy supplemented compound vitamins (OR = 0.761,95% CI = 0.485-0.923) and appropriate physical exercise (OR = 0.7535.95% CI = 0.512-0.913) It was the protective factor of early abortion. After multiple factors analysis, the sales profession (OR = 2.417), the history of spontaneous abortion (OR = 3.166), the history of active abortion (OR = 2.396), the night shift (OR = 1.473) and the stay-up (OR = 1.464) significantly increased the risk of abortion; and the body rearing exercise (OR = 0.735), supplemented with compound vitamins (OR = 0.7 61) is a protective factor for abortion. The risk allele C of the Foxp3 gene rs3761548 is of statistical significance in the distribution of the case group and the control group (Sup2 = 4.927, P = 0.012). The mutation homozygote CC was significantly higher in the abortion group than in the control group (Sup2 = 6.387, P = 0.011), and the recessive genetic model increased the risk of the disease (OR = 1.275,95% CI = 1.012-1.417), and the rs595328 of Foxp3 0-site was not associated with early-trimester abortion. CTLA- 4 at 2 sites rs5742909. rs231 775 was not associated with the early abortion of pregnancy.3 Logistic regression model was used to analyze the interaction between the two points, and the factors such as occupation, natural abortion history, active abortion history, night shift, stay up, physical exercise, and compound vitamin were adjusted. The results showed that there was no interaction between the four points. The four-point and environmental risk factors were analyzed by Logistic regression model. The best interaction model was found to be the four-factor interaction model of natural abortion history, night shift, stay-up, rs3761548, and the accuracy of the model was 0.62. The verification rate was 90% and the model P value was 0.01.4. The serum DBP level of the garment sales case group[0.454-0.386 (. mu.g/ ml)] was higher than that in the non-sales control group[0.216-0.155 (. mu.g/ ml)], and the difference was of statistical significance (this = 0.001); in the peripheral blood of the garment sales case group and in the decidua tissue, Treg[(0.937-0.212)%, (1.136-0.428)%)] was significantly lower than the non-sales control group[(1.327-0.438)%, (2.115-0.498)%)], The difference was statistically significant (P = 0.000 for both groups). The serum DBP level in the garment sales group was compared to that of the peripheral blood There was a negative correlation between the number of Treg (P0.05). Conclusion:1 In the female population of the Chinese Han nationality, the sales profession, the history of spontaneous abortion, the history of active abortion, the night shift and the frequent stay-up can increase significantly. The risk of natural abortion in the early stage of pregnancy; and the pre-pregnancy supplementary compound Vitamin and appropriate physical exercise can reduce the risk of spontaneous abortion. The rs3761548 site of Foxp3 gene can increase the risk of early spontaneous abortion of female pregnant women during the childbearing potential of Chinese Han population; and the history of spontaneous abortion, night shift, stay up, and rs376 There is an interactive effect between the four factors at the site of 1548, which can increase the risk of abortion. The level of DBP of the women in the garment sales is higher than that of the non-sales female, which may affect the number of peripheral blood Treg; the early spontaneous abortion may be in the tissue of the maternal interface
【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R714.21

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