Post-graduate Program in Genetics and Molecular Biology, Department of Genetics, Biosciences Institute, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Post-graduate Program in Child and Adolescent Health, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Syst Biol Reprod Med. 2021 Dec;67(6):450-462. doi: 10.1080/19396368.2021.1965673. Epub 2021 Sep 9.
Recurrent pregnancy loss (RPL) is the most common reproductive failure, reaching 1-5% of women throughout their lives, and having unknown etiology in 50% of the cases. In humans, (pidermal rowth actors & ripto/RL-1/ryptic) gene family is composed by and , two developmental genes. The aim of this study was to investigate the role of EGF-CFC on RPL. To this, multiple approaches were performed; we conducted an expression analysis of and using publicly available data from Gene Omnibus Expression (GEO), systems biology analyses and functional prediction; and a molecular analysis carried out in a case-control study. Our GEO analysis showed a decrease in expression in the endometrium (p=0.049) and expression in placenta (p=0.015) of women with RPL. Network analysis, gene ontology and literature pointed to a strong connection between gene family to pathways that play key roles during pregnancy, including TGF-β, c-Src/MAPK/AKT, Notch, TNFα, IFNγ and IL-6. A pathogenicity score developed for this gene family showed that the c.-14+1429T>C (rs3806702) variant in the and the p.Arg47Gln (rs201431919) variant in gene would be the ones with the highest deleterious effect for RPL. In the case-control study, which involved 149 women with RPL and 159 controls, no statistical difference was observed in the allele and genotype distributions of the variants studied in the two groups. In this study, we performed extensive bioinformatics analysis for biomarker prioritization followed by experimental validation of proposed selected markers. Although there is no statistical difference in the frequencies of these variants between RPL and controls, the expression analysis results suggest that and genes might play a role in RPL. In addition, systems biology analyzes raise the hypothesis that genes in other signaling pathways that may be related to RPL as good candidates for future studies. RPL: recurrent pregnancy loss; : pidermal rowth actors - ripto/RL-1; GEO: Gene Omnibus Expression; KEGG: Kyoto Encyclopedia of Genes and Genomes.
复发性流产（RPL）是最常见的生殖失败，在女性一生中达到 1-5%，其中 50%的病因不明。在人类中，(表皮生长因子 CFC 家族& ripto/RL-1/隐匿)基因家族由 和 组成，两个发育基因。本研究旨在探讨 EGF-CFC 在 RPL 中的作用。为此，我们进行了多种方法的研究；我们使用来自基因表达综合数据库（GEO）的公共数据进行了 和 的表达分析，进行了系统生物学分析和功能预测；并在病例对照研究中进行了分子分析。我们的 GEO 分析显示，RPL 女性的子宫内膜中 的表达减少（p=0.049），胎盘 的表达减少（p=0.015）。网络分析、基因本体和文献表明， 基因家族与在妊娠过程中发挥关键作用的途径之间存在很强的联系，包括 TGF-β、c-Src/MAPK/AKT、Notch、TNFα、IFNγ和 IL-6。为该基因家族开发的致病性评分显示， 中的 c.-14+1429T>C(rs3806702)变体和 中的 p.Arg47Gln(rs201431919)变体将是对 RPL 具有最高有害影响的变体。在涉及 149 名 RPL 女性和 159 名对照的病例对照研究中，在所研究的两组中，变体的等位基因和基因型分布没有统计学差异。在本研究中，我们进行了广泛的生物信息学分析，以进行生物标志物的优先级排序，然后对提出的候选标记进行实验验证。尽管在 RPL 和对照组之间这些变体的频率没有统计学差异，但表达分析结果表明 和 基因可能在 RPL 中发挥作用。此外，系统生物学分析提出了这样的假设，即其他信号通路中的基因可能与 RPL 有关，是未来研究的良好候选基因。RPL：复发性流产；：表皮生长因子 CFC 家族& ripto/RL-1；GEO：基因表达综合数据库；KEGG：京都基因与基因组百科全书。
