Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.
Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh.
Autoimmun Rev. 2018 Mar;17(3):226-243. doi: 10.1016/j.autrev.2017.10.014. Epub 2018 Jan 19.
Antiphospholipid Syndrome (APS) is an autoimmune multifactorial disorder. Genetics is believed to play a contributory role in the pathogenesis of APS, especially in thrombosis development and pregnancy morbidity. In the last 20 years, extensive research on genetic contribution on APS indicates that APS is a polygenic disorder, where a number of genes are involved in the development of its clinical manifestations.
The aim of this systematic review is to evaluate the genetic risk factors in thrombotic primary APS. Additionally, to assess the common molecular functions, biological processes, pathways, interrelations with the gene encoded proteins and RNA-Seq-derived expression patterns over different organs of the associated genes via bioinformatic analyses.
Without restricting the year, a systematic search of English articles was conducted (up to 4th September 2017) using Web of Science, PubMed, Scopus, ScienceDirect and Google Scholar databases. Eligible studies were selected based on the inclusion criteria. Two researchers independently extracted the data from the included studies. Quality assessment of the included studies was carried out using a modified New-Castle Ottawa scale (NOS).
From an initial search result of 2673 articles, 22 studies were included (1268 primary APS patients and 1649 healthy controls). Twenty-two genes were identified in which 16 were significantly associated with thrombosis in primary APS whereas six genes showed no significant association with thrombosis. Based on the NOS, 14 studies were of high quality while 6 were low quality studies. From the bioinformatic analyses, thrombin-activated receptor activity (q = 6.77 × 10), blood coagulation (q = 2.63 × 10), formation of fibrin clot (q = 9.76 × 10) were the top hit for molecular function, biological process and pathway categories, respectively. With the highest confidence interaction score of 0.900, all of the thrombosis-associated gene encoded proteins of APS were found to be interconnected except for two. Based on the pathway analysis, cumulatively all the genes affect haemostasis [false discovery rate (FDR) = 1.01 × 10] and the immune system [FDR = 9.93 × 10]. Gene expression analysis from RNA-Seq data revealed that almost all the genes were expressed in 32 different tissues in the human body.
According to our systematic review, 16 genes contribute significantly in patients with thrombotic primary APS when compared with controls. Bioinformatic analyses of these genes revealed their molecular interconnectivity in protein levels largely by affecting blood coagulation and immune system. These genes are expressed in 32 different organs and may pose higher risk of developing thrombosis anywhere in the body of primary APS patients.
抗磷脂综合征（APS）是一种自身免疫性多因素疾病。遗传被认为在 APS 的发病机制中起重要作用，尤其是在血栓形成和妊娠发病机制中。在过去的 20 年中，大量关于 APS 遗传贡献的研究表明，APS 是一种多基因疾病，许多基因参与其临床表现的发展。
本系统综述旨在评估血栓形成性原发性 APS 的遗传危险因素。此外，通过生物信息学分析，评估相关基因在不同器官的 RNA-Seq 衍生表达模式中的常见分子功能、生物学过程、途径、与基因编码蛋白的相互关系。
不限制年份，使用 Web of Science、PubMed、Scopus、ScienceDirect 和 Google Scholar 数据库对英文文章进行了系统搜索（截至 2017 年 9 月 4 日）。根据纳入标准选择符合条件的研究。两位研究人员独立从纳入的研究中提取数据。使用改良的纽卡斯尔渥太华量表（NOS）对纳入研究进行质量评估。
从最初的 2673 篇文章中，有 22 项研究入选（1268 例原发性 APS 患者和 1649 例健康对照）。在 22 个基因中，有 16 个基因与原发性 APS 血栓形成显著相关，而 6 个基因与血栓形成无关。根据 NOS，14 项研究为高质量研究，6 项为低质量研究。通过生物信息学分析，凝血酶激活受体活性（q = 6.77 × 10）、血液凝固（q = 2.63 × 10）、纤维蛋白凝块形成（q = 9.76 × 10）分别是分子功能、生物学过程和途径分类的最高命中。APS 血栓形成相关基因编码蛋白的置信度互作评分最高为 0.900，除两个外，所有蛋白均相互关联。基于途径分析，累积所有基因均影响止血[假发现率（FDR）= 1.01 × 10]和免疫系统[FDR = 9.93 × 10]。RNA-Seq 数据的基因表达分析显示，几乎所有基因都在人体 32 种不同组织中表达。
根据我们的系统综述，与对照组相比，16 个基因在血栓形成性原发性 APS 患者中显著表达。对这些基因的生物信息学分析表明，它们在蛋白质水平上的分子相互连接主要是通过影响血液凝固和免疫系统。这些基因在 32 种不同的器官中表达，可能会使原发性 APS 患者全身任何部位发生血栓形成的风险更高。
