埃及肾病综合征患儿肿瘤坏死因子-α基因多态性及单倍型。

Tumor necrosis factor alpha gene polymorphisms and haplotypes in Egyptian children with nephrotic syndrome.

机构信息

Pediatrics Department, Faculty of Medicine, Zagazig University, Egypt.

Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt.

出版信息

Cytokine. 2018 Feb;102:76-82. doi: 10.1016/j.cyto.2017.06.021. Epub 2017 Aug 10.

DOI:10.1016/j.cyto.2017.06.021

PMID:28803697

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

摘要

背景

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。

方法

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。

结果

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。