复发性流产遗传学病因研究及凝血因子V Leiden突变与复发性流产关系研究的Meta分析

发布时间：2018-01-14 01:21

本文关键词：复发性流产遗传学病因研究及凝血因子V Leiden突变与复发性流产关系研究的Meta分析　出处：《华中科技大学》2014年博士论文　论文类型：学位论文

【摘要】：目的：探讨RPL的遗传学病因,以及SNP-array技术在RPL患者遗传学病因诊断中的应用。材料和方法：收集2012年1月-2014年1月因复发性流产就诊于我院生殖中心门诊及入住计划生育病房患者的流产组织,使用SNP-array对流产组织进行分析,从而发现导致RPL的病因。结果：共对10例RPL患者的流产组织使用SNP-array进行染色体分析,2例(20%)未见明显异常,8例(80%)有异常。异常染色体中,5例为染色体三体(1例为2号染色体三体,1例为13号染色体3体,1例为21号染色体三体,2例为22号染色体三体),占染色体异常的总人数的62.5%,5例为染色体结构异常(包括3例片段缺失及2例单亲二倍体)占染色体异常总人数的62.5%,同时具有染色体数目和结构异常的有2例(1例为22号染色体三体及11号染色体杂合性缺失,1例为13号染色体三体及10号染色体微小片段缺失),占染色体异常总人数的25%。结论：染色体异常是导致RPL的常见原因,在各种染色体异常中以染色体的多体性改变最为常见,单核苷酸多态性微阵列技术以其高检出率及高分辨率的优势为复发性流产遗传学病因的诊断提供了更好的方法。目的：探讨凝血因子V Leiden突变与复发性流产的关系。方法：在PubMed, Embase,万方,维普等中外文数据库中,检索研究凝血因子VLeiden突变与复发性流产关系的文献。由两位独立的研究人员根据纳入标准和排除标准对获得的文献进行筛选,完成筛选后进行数据的提取,将提取的数据信息录入事先设计好的标准化表格中,最终使用RevMan5.2软件对纳入的文献进行Meta分析。结果：最终纳入21篇文献,在总体分析中,无论是FVLG1691AGA基因型、纯AA基因型、GA+AA基因型还是A等位基因频率,病例组导致复发性流产的风险均高于对照组,且有统计学意义,OR值分别为2.12(95%CI,1.70-2.64; P 0.00001),5.59(95%CI,1.84-16.96; P=0.002),1.84(95%CI,1.34-2.54; P=0.0002),1.79(95%CI,24-2.59). 在亚组分析中,针对人种进行的分析时,在高加索人种中,FVLG1691AGA基因型、GA+AA基因型、A等位基因频率病例组导致复发性流产的风险均比对照组高,且有统计学意义,OR值分别为1.98(95%CI,1.51-2.60; P0.0001),1.75(95%CI,1.22-2.49; P0.002)1.70(95%CI,1.12-2.57; P=0.01); FVLG1691A AA基因型与RPL也有关,但没有统计学意义,OR3.26(95%CI,0.95-11.18; P=0.06)。在对混合人种进行的FVL G1691A GA基因型、GA+AA基因型分析中,病例组导致复发性流产的风险均较对照组高,OR值分别为2.40(95%CI,1.64-3.52; P0.00001),2.71(95%CI,1.86-3.95; P0.00001);该亚组有一篇文献对FVL G1691A AA基因型进行检测OR87(95%CI,12-627;P0.001); FVLG1691AGA+AA基因型与RPL相关,但没有统计学意义,OR1.97(95%CI,0.97-4.00; P=0.06)。在不同妊娠时期流产的分析中,妊娠早期的研究中,FVL G1691AGA基因型、AA基因型、GA+AA基因型以及A等位基因频率,病例组较对照组均与复发性流产的关系明显,OR值分别为1.77(95%CI,1.18-2.65; P=0.006),9.51(95%CI,2.23-40.56; P=0.002),1.79(95%CI,1.13-2.86;P=0.001),1.71(95%CI,1.05-2.79; P=0.03)。对妊娠中期流产,FVLG1691AGA基因型、GA+AA基因型及A等位基因频率,病例组导致复发性流产的风险均较对照组高,且都具有统计学意义,OR值分别为4.91(95%CI,3.24-7.45; P0.00001),5.81(95%CI,3.85-8.74; P0.0001),3.83(95%CI,1.92-7.62; P=0.0001),该亚组有一篇文献对FVL G1691AAA基因型进行分析,OR168(95%CI,22-879;P0.0001)。结论：从本meta分析结果来看,FVL与RPL有较强的关系,该突变GA基因型导致复发性流产的风险为正常人的2倍,AA基因型则可达5.6倍,携带A等位基因导致复发性流产风险为正常人的2倍。同时我们发现该突变存在人种的遗传异质性,高加索人种和混合人种中该突变与RPL均相关,混合人种携带FVL导致复发性流产的几率更高。在早期和中期妊娠中,FVL均可导致复发性流产,且在中期流产的危险性更高。由于RPL是一种多因素共同作用的疾病,需要更多研究来对其病因进行探究。
[Abstract]:Objective: To investigate the genetic causes of RPL and the application of SNP-array in the genetic diagnosis of RPL patients.
Materials and methods: We collected the aborted tissues from the reproductive center clinic and the family planning ward in January 2012 -2014 January, and analyzed the abortion tissues by SNP-array, and found the cause of RPL.
Results: a total of abortion tissue of 10 cases with RPL chromosome analysis using SNP-array, 2 cases (20%) had no obvious abnormalities, 8 cases (80%) had abnormal chromosome abnormalities. In 5 cases (1 cases of trisomy trisomy of chromosome 2, 1 cases of chromosome 13, 3, 1 cases trisomy of chromosome 21, 2 cases of trisomy 22), the total number of chromosome abnormalities in 62.5%, 5 cases of chromosome structural abnormalities (including 3 cases of deletion and 2 cases of uniparental disomy) accounted for 62.5% of the total number of chromosomal abnormalities, and chromosome number and structural abnormality in 2 cases (1 cases trisomy of chromosome 22 and chromosome 11 LOH, 1 cases of trisomy 13 and loss of chromosome 10, chromosome abnormalities accounted for tiny fragments) the total number of 25%.
Conclusion: chromosomal abnormalities are common causes of RPL, in a variety of chromosomal abnormalities in chromosome polysomy change is most common, single nucleotide polymorphism microarray technology to the diagnosis of high detection rate and high resolution advantages for recurrent spontaneous abortion etiology provides a better way.
Objective: To investigate the relationship between the mutation of coagulation factor V Leiden and recurrent abortion.
Methods: PubMed, Embase, Wanfang, VIP and other foreign language database, retrieval of coagulation factor VLeiden mutation and recurrent abortion relation literature. By two independent researchers according to inclusion criteria and exclusion criteria of the literature screening, completed after screening the data extraction, data entry information extraction the advance design standard form in the final, RevMan5.2 software was used for Meta analysis of included literature.
Results: a total of 21 articles in the overall analysis, both the FVLG1691AGA genotype, pure AA genotype, GA+AA genotype and A allele frequency, resulting in the risk of recurrent spontaneous abortion cases were higher than the control group, and there was statistical significance, OR values were 2.12 (95% CI, 1.70-2.64; P 0.00001), 5.59 (95%CI, 1.84-16.96; P=0.002), 1.84 (95%CI, 1.34-2.54; P=0.0002), 1.79 (95%CI, 24-2.59).
In the subgroup analysis, according to the analysis of the race, in the Caucasian population, FVLG1691AGA genotype, GA+AA genotype and A allele frequency were risk of recurrent spontaneous abortion were higher than the control group, and there was statistical significance, OR values were 1.98 (95%CI, 1.51-2.60; P0.0001, 1.75) (95%CI, 1.22-2.49; P0.002) 1.70 (95%CI, 1.12-2.57; P=0.01; FVLG1691A) AA genotype and RPL, but no statistical significance (OR3.26, 95%CI, 0.95-11.18; P=0.06). In FVL G1691A GA based on a mixed race for type analysis of GA+AA genotype in case group, leading to the risk of recurrent abortion is higher than the control group, the OR values were 2.40 (95%CI, 1.64-3.52; P0.00001), 2.71 (95%CI, 1.86-3.95; P0.00001); the sub group has a review on FVL G1691A AA to detect OR87 genotype (95%CI, 12-627; P0.001); the FVLG1691AGA+AA genotype is associated with RPL, but no There was statistical significance (95%CI, OR1.97, 0.97-4.00; P=0.06). In the analysis of abortion during different stage of pregnancy in early pregnancy in the study, FVL G1691AGA genotype, AA genotype, GA+AA genotype and A allele frequency were compared with the control group were associated with recurrent spontaneous abortion, OR respectively. 1.77 (95%CI, 1.18-2.65; P=0.006), 9.51 (95%CI, 2.23-40.56; P=0.002), 1.79 (95%CI, 1.13-2.86; P=0.001), 1.71 (95%CI, 1.05-2.79; P=0.03). On the second trimester abortion, FVLG1691AGA genotype, GA+AA genotype and A allele frequencies, cases cause the risk of recurrent spontaneous abortion is higher than the control group, and have statistical significance, OR values were 4.91 (95%CI, 3.24-7.45; P0.00001), 5.81 (95%CI, 3.85-8.74; P0.0001), 3.83 (95%CI, 1.92-7.62; P=0.0001), the sub group has a literature analysis of FVL genotype G1691AAA, OR168 (95%CI, 22-879; P0.0001).
Conclusion: from the results of meta analysis, there is a strong relationship between FVL and RPL, the GA gene mutation type lead to 2 times the risk of recurrent spontaneous abortion for normal people, AA genotype is up to 5.6 times, the A allele leads to recurrent miscarriage risk is 2 times normal. At the same time, we found that the mutation and genetic heterogeneity in race, Caucasian and mixed races were related to the mutation and RPL, mixed race with FVL lead to the risk of recurrent miscarriage is higher. In the early and mid pregnancy, FVL can lead to recurrent spontaneous abortion, and in danger of second trimester abortion higher. Because RPL is a function of a a multi factor disease, more research is needed to explore its causes.

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R714.21

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