【摘要】：目的： 早期自然流產(early miscarriage, EM)雖經大量研究,由于病因復雜,機制不清,缺乏預防及早期診斷、早期治療的方法。隨著對基因功能研究的深入,基因和環(huán)境與疾病的關聯已經成為疾病研究的新策略。目前關于EM的研究較為局限,雖已知自身免疫紊亂在EM發(fā)病過程中具有重要作用,但其發(fā)生發(fā)展過程中環(huán)境因素的致病風險、環(huán)境與基因交互作用的影響及其與機體自身免疫紊亂的關系研究報道較少。為此采用流行病學調查、環(huán)境與基因交互作用分析、免疫調節(jié)細胞檢測等研究方法,探討環(huán)境、基因、免疫等因素對EM的影響及其相互關聯,為闡明EM的危險因素、發(fā)病機制、早期預防和治療等提供相關科學依據。 研究方法： 1流行病學調查：應用基于醫(yī)院調查的病例對照研究方法,采用問卷調查方式,調查鄭州市三家省市級醫(yī)院640例妊娠早期流產患者和1280例中晚期正常圍產保健妊娠婦女生活環(huán)境情況,分析環(huán)境因素對妊娠、流產的影響。 2基因多態(tài)性及交互作用分析：對所有調查對象提取全基因組DNA,分析抑制性免疫調節(jié)基因Foxp3基因的兩個位點rs3761548、rs5953280和CTLA-4基因的2個位點rs231775和rs5742909的多態(tài)性,采用統計軟件SPSS21.0擬合Logistic和MDR軟件分析基因-基因、基因-環(huán)境的交互作用對流產的影響。 3血清PAEs及Treg檢測：以從事服裝銷售的女性EM患者65例和正常妊娠者49例、非銷售職業(yè)的EM患者65例和正常妊娠者70例為研究對象,采用流式細胞儀檢測外周血及流產胚胎蛻膜組織中調節(jié)性T淋巴細胞(Treg)的分布變化,采用高效液相色譜法檢測血清中鄰苯二甲酸酯類(PAEs)中鄰苯二甲酸二乙酯(DEP)、鄰苯二甲酸二丁酯(DBP)、苯二甲酸二異辛酯(DEHP)水平,初步探討環(huán)境污染物和Treg數量變化與EM的關系。 結果： 1銷售職業(yè)、自然流產史、主動流產史、熬夜、夜班可能是早期流產的風險因子：單因素Logistic回歸分析結果顯示,從事銷售(OR=2.417,95%CI=1.384～2.918)和財務職業(yè)(OR=1.632,95%CI=1.113～2.272)的女性易于自然流產；既往的自然流產史(OR=2.583,95%CI=1.197～4.069)和主動流產史(OR=1.872.95%CI=1.066～2.849)是妊娠早期流產的危險因素；經常值夜班(OR=1.473.95%CI=1.113～1.842)和經常熬夜(OR=1.464.95%CI=1.072～2.820)是妊娠早期流產的危險因素；孕前緊張(OR=1.345,95%CI=1.013～1.626)和工作壓力過大(OR=1.462,95%CI=1.172～1.716)也是流產的危險因素；而妊娠前補充復合維生素(OR=0.761,95%CI=0.485～0.923)和適當體育鍛煉(OR=0.735.95%CI=0.512～0.913)是妊娠早期流產的保護性因素。經多因素分析后,銷售職業(yè)(OR=2.417)、自然流產史(OR=3.166)、主動流產史(OR=2.396)、夜班(OR=1.473)、熬夜(OR=1.464)等5種因素顯著增加了流產的風險；而體育鍛煉(OR=0.735)、補充復合維生素(OR=0.761)則是流產的保護性因素。 2Foxp3基因rs3761548的風險等位基因C在病例組與對照組的分布差異有統計學意義(χ2=4.927,P=0.012)。突變純合子CC在流產組中顯著高于對照組(χ2=6.387,P=0.011),以及隱性遺傳模型能增加疾病的風險(OR=1.275,95%CI=1.012～1.417), Foxp3的rs5953280位點與妊娠早期流產無明顯關聯。CTLA-4的2個位點rs5742909. rs231775與妊娠早期流產無明顯關聯。 3用Logistic回歸模型分析兩兩位點間交互作用,調整了職業(yè)、自然流產史、主動流產史、夜班、熬夜、體育鍛煉、補充復合維生素等因素后,結果顯示四位點間均未見交互作用。用Logistic回歸模型分析四位點與環(huán)境風險因子進行一階交互作用,也未發(fā)現明顯的交互效應。當采用多因子降維法(multifactor dimensionality reduction, MDR)進行高階交互分析時,發(fā)現最佳的交互模型是自然流產史、夜班、熬夜、rs3761548的四因子交互模型,該模型的檢驗平衡集精度為0.62,交叉驗證率為90%,模型P值為0.01。 4服裝銷售病例組血清DBP水平[0.454±0.386(μg/ml)]高于非銷售對照組血清DBP水平[0.216±0.155(μg/ml)],差異有統計學意義(這=0.001);服裝銷售病例組外周血及蛻膜組織中Treg[(0.937±0.212)%,(1.136±0.428)%)]顯著低于非銷售對照組[(1.327±0.438)%,(2.115±0.498)%)],差異有統計學意義(兩組P=0.000)。服裝銷售組的血清DBP水平與其外周血Treg數量負相關(P0.05)。 結論： 1在中國漢族育齡期女性人群中,從事銷售職業(yè)、有自然流產史、主動流產史、夜班工作和經常熬夜能顯著增加妊娠早期自然流產的風險；而孕前補充復合維生素、適當的體育鍛煉則可以降低自然流產的風險。 2Foxp3基因的rs3761548位點可增加中國漢族育齡期女性妊娠早期自然流產的風險；而且自然流產史、夜班、熬夜以及rs3761548位點四因素之間存在交互效應,能增加流產風險。 3服裝銷售女性血清DBP水平高于非銷售女性,可能影響外周血Treg數量；早期自然流產可能與母胎界面組織內Treg數量減少有關,而與外周血Treg數量無顯著性關系。
[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
【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R714.21

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