本文選題：血管內(nèi)皮生長(zhǎng)因子（VEGF）　切入點(diǎn)：基因多態(tài)性　出處：《寧夏醫(yī)科大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：目的本研究旨在探討血管內(nèi)皮生長(zhǎng)因子（vascular endothelial growth factor,VEGF）基因rs699947(C/A),rs1570360(G/A)，rs833061(T/C)和rs3025039(C/T)四個(gè)多態(tài)性位點(diǎn)與中國(guó)寧夏地區(qū)漢族婦女復(fù)發(fā)性自然流產(chǎn)（recurrent spontaneous abortion, RSA）的相關(guān)性，并分析VEGF基因的四個(gè)SNP位點(diǎn)所構(gòu)建的單倍型與復(fù)發(fā)性自然流產(chǎn)之間的關(guān)聯(lián)性。 方法病例組選取2006年1月至2009年7月在寧夏醫(yī)科大學(xué)生殖與遺傳實(shí)驗(yàn)室進(jìn)行染色體檢查的復(fù)發(fā)性自然流產(chǎn)患者203例，年齡19-42歲，平均年齡27.63±4.44歲；對(duì)照組選取與病例組年齡相匹配的2008年1月至2010年10月在銀川市婦幼保健院正常分娩的女性190例，年齡20-36歲，平均年齡27.26±2.31歲。采用聚合酶鏈反應(yīng)-限制性片段長(zhǎng)度多態(tài)性（polymerase chain-reaction restricted fragment length polymorphism,PCR-RFLP）和等位基因特異性PCR（AS-PCR）技術(shù)檢測(cè)病例組與對(duì)照組VEGF基因四個(gè)位點(diǎn)多態(tài)性。用SPSS18.0統(tǒng)計(jì)軟件進(jìn)行卡方檢驗(yàn)及疾病相對(duì)危險(xiǎn)度的估計(jì)，計(jì)算和比較各組基因型頻率、等位基因頻率、比值比（OR）及95%可信區(qū)間（95%CI），分析VEGF基因四個(gè)SNPs位點(diǎn)與復(fù)發(fā)性自然流產(chǎn)的相關(guān)性，用Haploview軟件進(jìn)行連鎖不平衡及單倍體型分析，探討VEGF基因四個(gè)SNPs位點(diǎn)與復(fù)發(fā)性自然流產(chǎn)易感性之間的關(guān)聯(lián)。 結(jié)果①經(jīng)遺傳平衡定律檢驗(yàn)，VEGF基因的四個(gè)多態(tài)性位點(diǎn)中除rs1570360外，其余位點(diǎn)各基因型頻率分布均符合Hardy-Weinberg平衡法則，具有群體代表性。②VEGF基因rs833061的基因型與等位基因分布頻率在病例組和對(duì)照組中進(jìn)行比較，結(jié)果顯示差異均有統(tǒng)計(jì)學(xué)意義（P0.001）。VEGF基因rs3025039的基因型與等位基因分布頻率在病例組和對(duì)照組中進(jìn)行比較，結(jié)果顯示差異均有統(tǒng)計(jì)學(xué)意義（P0.01）。③VEGF基因rs699947、rs1570360位點(diǎn)各基因型頻率和等位基因頻率在病例組與對(duì)照組中的分布均無(wú)統(tǒng)計(jì)學(xué)意義（P0.05）。④VEGF基因rs699947、rs833061與rs3025039三個(gè)位點(diǎn)構(gòu)建的單倍型中有5種保護(hù)性單倍型在病例組與對(duì)照組中具有統(tǒng)計(jì)學(xué)意義（P0.05，OR1）；5種危險(xiǎn)致病單倍型在兩組中的分布具有統(tǒng)計(jì)學(xué)差異（P0.05，OR1）。 結(jié)論1、VEGF基因rs699947、rs1570360位點(diǎn)的基因多態(tài)性與寧夏漢族女性復(fù)發(fā)性自然流產(chǎn)的易感性無(wú)關(guān)。2、VEGF基因rs833061、rs3025039位點(diǎn)的基因多態(tài)性與復(fù)發(fā)性自然流產(chǎn)有一定的關(guān)聯(lián)性，攜帶rs833061T及rs3025039T等位基因的基因型可能是寧夏漢族女性復(fù)發(fā)性自然流產(chǎn)的易感因素。3、VEGF基因構(gòu)建的單倍型中，有5種單倍型可能是寧夏漢族女性復(fù)發(fā)性自然流產(chǎn)的保護(hù)性因素，有5種單倍型可能是寧夏漢族女性復(fù)發(fā)性自然流產(chǎn)的危險(xiǎn)性因素。 目的對(duì)VEGF基因多態(tài)性與復(fù)發(fā)性自然流產(chǎn)相關(guān)性研究的現(xiàn)有數(shù)據(jù)進(jìn)行評(píng)估和綜合。 方法通過(guò)文獻(xiàn)檢索收集國(guó)內(nèi)外數(shù)據(jù)庫(kù)自開庫(kù)至2013年11月公開發(fā)表的關(guān)于VEGF基因多態(tài)性與復(fù)發(fā)性自然流產(chǎn)相關(guān)性的病例-對(duì)照研究，剔除不符合要求的文獻(xiàn)，采用RevMan5.2軟件，根據(jù)文獻(xiàn)異質(zhì)性檢驗(yàn)結(jié)果，進(jìn)行固定效應(yīng)模型和隨機(jī)效應(yīng)模型的Meta分析。對(duì)不同納入標(biāo)準(zhǔn)的結(jié)果進(jìn)行了敏感性分析，用漏斗圖評(píng)估發(fā)表性偏倚。 結(jié)果納入符合標(biāo)準(zhǔn)的已發(fā)表文獻(xiàn)11篇、未發(fā)表文獻(xiàn)1篇（本研究），，其中涉及rs1570360(G/A)多態(tài)性的文獻(xiàn)11篇，涉及rs699947(C/A)多態(tài)性的文獻(xiàn)7篇，涉及rs3025039(C/T)多態(tài)性的文獻(xiàn)8篇。入選文獻(xiàn)無(wú)明顯偏倚，各文獻(xiàn)異質(zhì)性檢驗(yàn)顯示rs699947、rs3025039研究結(jié)果無(wú)顯著異質(zhì)性（P=0.56，I2=0%；P=0.18，I2=31%）；rs1570360（P=0.01，I2=67%）入選文獻(xiàn)存在顯著異質(zhì)性。Meta分析顯示rs1570360、rs699947與RSA無(wú)明顯相關(guān)性，合并OR及95%可信區(qū)間分別為1.16(0.96-1.41)、1.01(0.78-1.30)；rs3025039與RSA有一定的相關(guān)性，合并OR及95%可信區(qū)間為1.33(1.11-1.60)，P0.05。本次研究根據(jù)所收集資料的特點(diǎn)，對(duì)不同影響因素進(jìn)行了敏感性分析，分析結(jié)果與原結(jié)果相似，支持總樣本研究結(jié)果。 結(jié)論VEGF基因rs1570360、rs699947多態(tài)性與復(fù)發(fā)性自然流產(chǎn)（RSA）無(wú)明顯相關(guān)性，VEGF基因rs3025039多態(tài)性與復(fù)發(fā)性自然流產(chǎn)（RSA）存在一定的相關(guān)性。敏感性分析和發(fā)表性偏倚的識(shí)別結(jié)果表明，本次Meta分析結(jié)果穩(wěn)定、可靠，反映了近十年來(lái)VEGF基因rs1570360、rs699947、rs3025039與RSA關(guān)系的研究結(jié)果。
[Abstract]:The purpose of this study is to investigate the expression of vascular endothelial growth factor (vascular endothelial, growth factor, VEGF) gene rs699947 (C/A), rs1570360 (G/A), rs833061 (T/C) and rs3025039 (C/T) four polymorphic loci and the Han nationality women in Ningxia area Chinese recurrent natural runoff (recurrent spontaneous abortion, RSA) and the correlation. Correlation analysis between four SNP loci of VEGF gene constructed haplotype and recurrent spontaneous abortion.
Methods 203 cases of recurrent spontaneous abortion patients from January 2006 to July 2009 for chromosome examination in Ningxia Medical University were selected in the laboratory of reproductive and genetic group, age 19-42 years, mean age 27.63 + 4.44; control group were matched with the case group age from January 2008 to October 2010 in Yinchuan Maternal and Child Health-Care Center of normal pregnant women in 190 cases, age 20-36 years old. The average age of 27.26 + 2.31 years. Using polymerase chain reaction restriction fragment length polymorphism (polymerase chain-reaction restricted fragment length polymorphism, PCR-RFLP) and allele specific PCR (AS-PCR) group and control group cases detection VEGF gene four polymorphism. Chi square test and estimate the relative risk of disease using SPSS18.0 statistical software to calculate and compare the frequency of each genotype, allele frequency, odds ratio (OR) and 95% confidence Interval (95%CI), we analyzed the correlation between four SNPs loci of VEGF gene and recurrent spontaneous abortion. We used Haploview software to conduct linkage disequilibrium and haplotype analysis, and to explore the association between the four SNPs loci of VEGF gene and the susceptibility of recurrent spontaneous abortion.
The results of genetic equilibrium test, VEGF gene four polymorphism loci except for rs1570360, other sites of the genotype distribution was in accordance with Hardy-Weinberg law of balance, with a representative group. The VEGF gene rs833061 genotype and allele frequency distribution in the case group and control group were compared, the results showed that there were statistically significant differences (P0.001).VEGF gene rs3025039 genotype and allele frequency distribution in the case group and control group were compared, the results showed that there were statistically significant differences (P0.01). The VEGF gene rs699947, rs1570360 locus genotype distribution and allele frequencies in the case group and control group. There was no statistical significance (P0.05). The VEGF gene of rs699947, rs833061 and rs3025039 three locus haplotypes were constructed in 5 kinds of protective haplotypes in the case group and the control group. There were statistical significance (P0.05, OR1); the distribution of 5 types of risk haplotypes in the two groups was statistically different (P0.05, OR1).
Conclusion 1. VEGF gene rs699947, the susceptibility of rs1570360 polymorphism in Ningxia Han women with recurrent spontaneous abortion is independent of.2, VEGF gene rs833061, rs3025039 gene polymorphism is associated with the recurrent spontaneous abortion, genotypes carrying rs833061T and rs3025039T alleles may be the susceptible women of Han nationality in Ningxia recurrent spontaneous abortion factors.3, VEGF gene haplotypes, 5 haplotypes may be a protective factor in Ningxia Han women with recurrent spontaneous abortion, 5 haplotypes may be a risk factor in Ningxia Han nationality women with recurrent spontaneous abortion.
Objective to evaluate and integrate the existing data on the study of the association of VEGF gene polymorphism with recurrent spontaneous abortion.
A case-control study on the association between VEGF gene polymorphism and recurrent spontaneous abortion through the methods of literature retrieval collection of databases at home and abroad since the open library to published in November 2013, does not conform to the requirements of the literature, using RevMan5.2 software, based on the heterogeneity test, analysis of fixed effect model and random effect model of Meta. Different inclusion criteria were used to evaluate the sensitivity analysis, funnel plot of publication bias.
The results included in standard 11 were published and unpublished literature 1 (this study), including rs1570360 (G/A) polymorphism in 11 literatures related to rs699947 (C/A) polymorphism in 7 literatures related to rs3025039 (C/T) polymorphism in 8 literatures. The selected literature had no obvious bias. The results of heterogeneity test showed that rs699947, no significant heterogeneity of the results of rs3025039 (P=0.56, I2=0%; P=0.18, I2=31%); rs1570360 (P=0.01, I2=67%) significant heterogeneity in.Meta analysis showed that rs1570360 existed in the literature, rs699947 and RSA had no significant correlation with OR, and 95% confidence intervals were 1.16 (0.96-1.41). 1.01 (0.78-1.30); there is a certain correlation between rs3025039 and RSA, combined with OR and 95% with 1.33 confidence intervals (1.11-1.60), P0.05. of the study according to the characteristics of data, the effect of different factors in the sensitivity analysis, the results were similar with the original, Support the results of the total sample study.
Conclusion VEGF gene rs1570360, rs699947 polymorphism and recurrent spontaneous abortion (RSA) there is no significant correlation between VEGF gene rs3025039 polymorphism and recurrent spontaneous abortion (RSA). There is a correlation between the sensitivity analysis and publication bias in the recognition results show that the Meta analysis results are stable and reliable, reflects the past ten years VEGF gene rs1570360, rs699947, rs3025039 and RSA between the results.

【學(xué)位授予單位】：寧夏醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R714.21

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