Pediatrics Department, Faculty of Medicine, Zagazig University, Egypt.
Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt.
Cytokine. 2018 Feb;102:76-82. doi: 10.1016/j.cyto.2017.06.021. Epub 2017 Aug 10.
Nephrotic syndrome (NS) characterized by complex pathogenesis and clinical course with relapses; and needs novel breakthroughs for decades. Polymorphisms of cytokines genes including tumor necrosis factor alpha (TNF-α)may influence susceptibility to NS as well as different patients' steroid responses. In the current study, we demonstrated the potential roles of TNF-α promoter gene polymorphisms [-238, -308, -863] and haplotypes in susceptibility to childhood NS. Also, elucidating their possible influence on patients' steroid response and serum TNF-α level.
This case-control study included 150 children suffering from NS and 150 healthy children. Polymerase chain reaction- restriction-fragment length polymorphism (PCR-RFLP) was performed to evaluate different TNF-α gene polymorphism. TNF-α serum levels were assessed by ELISA.
Serum TNF-α levels were significantly higher in NS patients than in controls and in steroid resistant NS (SRNS) than in steroid sensitive NS (SSNS) (P<0.001 for each). The risk of NS in patients carrying TNF-α-238GA genotype, and TNF-α-308GA or AA genotypes and allele A was significantly increased compared to healthy children. While no significant association was detected between TNF-α-863 and NS. The risk of resistance to steroid therapy was significantly high in NS carrying TNF-α-238GA genotype and A allele, TNF-α-308, AA genotypes and A allele, and TNF-α-863CA, AA genotypes and A allele. The TNF-α GCG (-308/-863/-238) haplotype has protective roles against NS and steroid resistance. However, the risk of NS was significantly high in TNF-α AAG and AAA haplotype's carriers compared to healthy children. Additionally the risk of steroid resistance was significantly high in TNF-α AAA haplotype's NS carrier (OR (95%CI): 2.2 (1.19-4.36), P=0.01). Moreover, we found significant higher serum TNF-α levels NS patients including SSNS and SRNS carrying mutant allele TNF-α-238GA genotype, -308GA and AA and -863CA and AA wild genotype's carriers than in those GG, GG and CC respectively. Interstingely, TNF-α levels were significantly higher in healthy children carrying TNF-α(-308/-863/-238) [AAG and AAA haplotypes], NS cases carrying [ACA, AAG, AAA haplotypes], and in SSNS carrying [ACA and AAA haplotypes] than in those carrying GCG, haplotype of wild alleles.
This study reported, for the first time, that TNF-α promoter gene polymorphisms and/or haplotypes are risk factors of NS and resistance to steroid among Egyptian children.
肾病综合征（NS）以复杂的发病机制和临床病程为特征，存在复发情况，需要数十年来的新突破。细胞因子基因的多态性，包括肿瘤坏死因子-α（TNF-α），可能影响 NS 的易感性以及不同患者的激素反应。在本研究中，我们证明了 TNF-α启动子基因多态性[-238、-308、-863]和单倍型在儿童 NS 易感性中的潜在作用。并阐明了它们对患者激素反应和血清 TNF-α水平的可能影响。
这项病例对照研究包括 150 名患有 NS 的儿童和 150 名健康儿童。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）评估不同的 TNF-α基因多态性。通过酶联免疫吸附试验（ELISA）评估 TNF-α 血清水平。
NS 患者的血清 TNF-α 水平明显高于对照组，激素耐药性 NS（SRNS）患者的水平明显高于激素敏感性 NS（SSNS）患者（P<0.001）。与健康儿童相比，携带 TNF-α-238GA 基因型、TNF-α-308GA 或 AA 基因型和 A 等位基因的 NS 患者发生 NS 的风险显著增加。而 TNF-α-863 与 NS 之间没有显著相关性。携带 TNF-α-238GA 基因型和 A 等位基因、TNF-α-308AA 基因型和 A 等位基因以及 TNF-α-863CA、AA 基因型和 A 等位基因的 NS 患者对激素治疗的耐药性风险显著增加。TNF-αGCG（-308/-863/-238）单倍型对 NS 和激素耐药性具有保护作用。然而，与健康儿童相比，携带 TNF-αAAG 和 AAA 单倍型的 NS 患者发生 NS 的风险显著增加。此外，TNF-αAAA 单倍型 NS 患者对激素耐药的风险显著增加（OR（95%CI）：2.2（1.19-4.36），P=0.01）。此外，我们发现与携带野生型 TNF-α-238GA 基因型、-308GA 和 AA 基因型和-863CA 和 AA 野生基因型的 NS 患者相比，携带突变型 TNF-α-238GA 基因型、-308GA 和 AA 基因型和-863CA 和 AA 野生基因型的 NS 患者血清 TNF-α 水平显著升高（SSNS 和 SRNS）。有趣的是，与携带 TNF-α（-308/-863/-238）野生等位基因的 GCG 单倍型相比，携带 TNF-α（-308/-863/-238）[AAG 和 AAA 单倍型]的健康儿童、携带 [ACA、AAG、AAA 单倍型]的 NS 病例以及携带 [ACA 和 AAA 单倍型]的 SSNS 患者的 TNF-α 水平显著升高。
本研究首次报道，TNF-α启动子基因多态性和/或单倍型是埃及儿童 NS 和激素耐药的危险因素。
