AlFadhli Suad, Ghanem Aqeel A M, Nizam Rasheeba
Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, Kuwait.
Department of Rheumatology, Mubarak Al-Kabeer Hospital, Ministry of Health, Kuwait.
Int J Rheum Dis. 2016 Jan;19(1):55-64. doi: 10.1111/1756-185X.12745. Epub 2015 Sep 25.
Systemic lupus erythematosus (lupus) is an autoimmune disease characterized by multiorgan pathology, accelerated apoptosis and hyper-autoantibody production against self-components. The root cause of lupus remains unknown, although multiple susceptibility factors have been reported in different ethnic group.
We aimed to explore the genome-wide differential expression spectrum of lupus and its severe form lupus nephritis (LN) in Arab females.
A total of 98 subjects: 40 lupus, 18 LN and 40 age/gender/ethnically matched healthy controls (HC) were recruited. Carefully chosen subjects (n = 11) were employed for whole human-genome expression profiling using high-density Human Exon 1.0.ST arrays (Affymetrix) and statistical analysis was carried out using appropriate software. Validation cohorts (n = 98) were investigated to quantify the expression of the nine selected candidate genes relative to GAPDH as endogenous control.
Genome-wide differential analysis revealed seven candidate genes in lupus and 36 in LN, when individually compared to HC (anova Welch t-test, P ≤ 0.005, Tukey's honestly post hoc analysis). Analysis of differentially expressed genes with a fold change of 2, revealed 16 Gene Ontology terms satisfying a P ≤ 0.05. We further detected five distinct inflammatory and metabolic pathways such as TWEAK, osteopontin, endochondral ossification, fluropyrimidine activity and urea cycle and metabolism of amino groups that significantly contribute to the pathogenesis of lupus (P < 0.05). Validation of selected candidate genes (IRF9, ABCA1, APOBEC3, CEACAM3, OSCAR, TNFA1P6, MMP9, SLC4A1) revealed significant differences in expression, indicating their promissory role in the pathogenesis of lupus.
Our study provides central gene regulators of therapeutic potential, indicating the future prospects of the study.
系统性红斑狼疮（狼疮）是一种自身免疫性疾病，其特征为多器官病变、细胞凋亡加速以及针对自身成分的自身抗体过度产生。尽管在不同种族群体中已报道了多种易感因素，但狼疮的根本病因仍不清楚。
我们旨在探索阿拉伯女性中狼疮及其严重形式狼疮性肾炎（LN）的全基因组差异表达谱。
共招募了98名受试者：40名狼疮患者、18名LN患者以及40名年龄、性别和种族匹配的健康对照（HC）。使用高密度人类外显子1.0.ST阵列（Affymetrix）对精心挑选的受试者（n = 11）进行全人类基因组表达谱分析，并使用适当软件进行统计分析。对验证队列（n = 98）进行研究，以量化相对于作为内参的甘油醛-3-磷酸脱氢酶（GAPDH）的9个选定候选基因的表达。
与HC单独比较时（方差分析的韦尔奇t检验，P≤0.005，Tukey真实事后分析），全基因组差异分析在狼疮中发现了7个候选基因，在LN中发现了36个候选基因。对变化倍数为2的差异表达基因进行分析，发现16个基因本体术语满足P≤0.05。我们进一步检测到5条不同的炎症和代谢途径，如肿瘤坏死因子样弱凋亡诱导因子（TWEAK）、骨桥蛋白、软骨内成骨、氟嘧啶活性以及尿素循环和氨基代谢，这些途径对狼疮的发病机制有显著贡献（P < 0.05）。对选定候选基因（干扰素调节因子9（IRF9）、三磷酸腺苷结合盒转运体A1（ABCA1）、载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3）、癌胚抗原相关细胞黏附分子3（CEACAM3）、破骨细胞刺激因子（OSCAR）、肿瘤坏死因子α诱导蛋白6（TNFA1P6）、基质金属蛋白酶9（MMP9）、溶质载体家族4成员1（SLC4A1））的验证显示表达存在显著差异，表明它们在狼疮发病机制中具有潜在作用。
我们的研究提供了具有治疗潜力的核心基因调节因子，指明了该研究的未来前景。
