Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression
Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression
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DOI：
10.1016/j.gene.2018.03.095
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发表时间：
2018-06-30
期刊：
影响因子：
3.5
通讯作者：
Ganai, Bashir A.
中科院分区：
文献类型：
--
作者：
Hameed, Iqra;Masoodi, Shariq R.;Ganai, Bashir A.
背景：糖尿病肾病是糖尿病患者死亡率的最强预测因素。即使在调整可改变和不可改变危险因素的潜在混杂影响之后，明显肾病的发展也涉及重要的个体差异。全基因组转录组研究报告了炎症信号通路的激活，并且越来越多的迹象表明遗传因素的作用。方法：我们在 1326 名不相关受试者中筛选了三种细胞因子基因（TNF-α、IL-6 和 IL-β）的 9 种遗传变异，其中包括健康对照（n = 464）、患有肾病的 2 型糖尿病患者 （DN，n = 448）和无肾病的 2 型糖尿病（T2D，n = 414）通过序列特异性扩增。使用实时定量 PCR (RT-qPCR) 的相关性研究和相对基因表达阐明了 SNP 的功能含义。结果：个体 SNP 分析显示 IL-1 beta rs16944-TT 基因型（OR = 3.51，95%CI = 2.36-5.21，P = 0.001）和 TNF-α rs1800629-AA 的关联性最高 分别与 T2D 和 DN 的基因型（OR = 2.75，95% CI = 1.64-4.59，P = 0.001）。单倍型频率显示 T2D 受试者中的 7 个组合和 DN 受试者中的 4 个组合具有显着风险。 T2D 和 DN 的最高风险分别与 GGTGAGTTT（OR = 4.25，95%CI = 3.3-14.20，P = 0.0016）和 GACGACCTT（OR = 21.3，95%Cl = 15.1-28.33，P = 0.026）单倍型相关。 RT-qPCR 的相对表达显示，与对照组相比，病例中细胞因子表达增加。 DN 中 TNF-α 的表达增加了四倍以上（n 倍 = 4.43 +/- 1.11）。 TNF-α、IL-6 和 IL-1 β 转录物水平受启动子区域 SNP 显着调节。结论：本研究表明细胞因子 TNF-α、IL-6 和 IL-1 β 基因启动子多态性和转录物水平调节与糖尿病受试者肾病易感性之间存在密切关联。
Background: Diabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors.Methods: We screened nine genetic variations in three cytokine genes (TNF-alpha, IL-6 and IL beta) in 1326 unrelated subjects comprising of healthy controls (n = 464), type 2 diabetics with nephropathy (DN, n = 448) and type 2 diabetes without nephropathy (T2D, n = 414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR).Results: Individual SNP analysis showed highest association of IL-1 beta rs16944-TT genotype (OR = 3.51, 95%CI = 2.36-5.21, P = 0.001) and TNF-alpha rs1800629-AA genotype (OR = 2.75, 95% CI = 1.64-4.59, P = 0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR = 4.25, 95%CI = 3.3-14.20, P = 0.0016) and GACGACCTT (OR = 21.3, 95%Cl = 15.1-28.33, P = 0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-alpha expression was increased by more than four-folds (n-fold = 4.43 +/- 1.11) in DN. TNF-alpha, IL-6 and IL-1 beta transcript levels were significantly modulated by promoter region SNPs.Conclusions: The present study implicates a strong association between cytokine TNF-alpha, IL-6 and IL-1 beta gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects.