Association of -308 TNF-α promoter polymorphism with type 1 diabetes in North Indians
Association of -308 TNF-α promoter polymorphism with type 1 diabetes in North Indians
复制标题
DOI：
10.1111/j.1744-313x.2006.00632.x
复制
发表时间：
2006-12-01
影响因子：
2.2
通讯作者：
Kapuria, V.
中科院分区：
文献类型：
--
作者：
Das, S. N.;Baniasadi, V.;Kapuria, V.
肿瘤坏死因子α（TNF-α）是一种具有强效免疫调节活性的多效性细胞因子。在人类中，TNF-α基因位于染色体6p 21。在高度多态性的人类白细胞抗原（HLA）基因复合物的区域中，TNF-α的遗传变异性被广泛地牵涉到该基因的改变的表达中，导致不同的炎性病症和自身免疫性疾病，包括1型糖尿病。我们评估了TNF-α启动子-308和-238位点多态性与1型糖尿病的相关性，并将其与北印度受试者血清和脂多糖激活的外周血单核细胞中TNF-α的产生相关。采用聚合酶链反应-限制性片段长度多态性分析方法，使用NcoI和BglII限制性内切酶对130例患者和133例正常人进行基因分型。1型糖尿病患者-308位点A等位基因和AG基因型频率显著高于对照组（Pc= 0.000248和0.000438），而-238位点两组间差异无统计学意义。在患者中，− 238位点的A等位基因频率非常罕见（< 2%），在对照组中不存在。与-308位点的AG基因型相比，-308位点的AG基因型与外周血（P< 0.001）以及基础水平（P< 0.05）和脂多糖刺激后外周血单核细胞中相对较高的TNF-α产生相关。GG基因型。本研究的结果表明，-308启动子位点A等位基因的频率较高可能与TNF-α基因的高表达有关，从而导致北印度人对1型糖尿病的易感性增加。
Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with a potent immunomodulatory activity. In humans, TNF-α gene is located on chromosome 6p21. 31 in the region of highly polymorphic human leucocyte antigen (HLA) gene complex, hence the genetic variability of TNF-α has been widely implicated in the altered expression of the gene leading to different inflammatory conditions and autoimmune diseases including type 1 diabetes. We assessed the association of TNF-α promoter polymorphisms at− 308 and− 238 sites with type 1 diabetes and correlated it with TNF-α production in the serum and by the lipopolysaccharide-activated peripheral blood mononuclear cells in North Indian subjects. Genotyping was performed on 130 patients and 133 normal subjects by polymerase chain reaction–restriction fragment length polymorphism analysis using NcoI and BglII restriction endonucleases. The frequency of A allele and AG genotype at− 308 site was significantly higher in patients with type 1 diabetes than that of the controls (Pc= 0.000248 and 0.000438, respectively) while no significant difference was observed at− 238 site between the two groups. The frequency of A allele at− 238 site was very rare (< 2%) among the patients and was absent in the control group. The AG genotype at− 308 site was associated with relatively higher production of TNF-α in the peripheral blood (P< 0.001), as well as by the peripheral blood mononuclear cells both at the basal level (P< 0.05) and after stimulation with lipopolysaccharide as compared to the− 308 GG genotype. The results of the present study suggest that higher frequency of A allele at the− 308 promoter site may be related to higher expression of TNF-α gene consequently leading to increased susceptibility to type 1 diabetes in North Indians.