Jamil Kaiser, Jayaraman Archana, Ahmad Javeed, Joshi Sindhu, Yerra Shiva Kumar
Genetics Department, Bhagwan Mahavir Medical Research Centre, 10-1-1, Mahavir Marg, AC Guards, Hyderabad 500004, Telangana, India.
Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Buddha Bhawan, 6th Floor, M.G. Road, Secunderabad 500003, Telangana, India.
Saudi J Biol Sci. 2017 Sep;24(6):1195-1203. doi: 10.1016/j.sjbs.2016.05.012. Epub 2016 May 25.
Several reports document the role of tumor necrosis factor alpha () and lipid metabolism in the context of acute inflammation as a causative factor in obesity-associated insulin resistance and as one of the causative parameter of type 2 diabetes mellitus (T2DM). Our aim was to investigate the association between -308G/A and -238G/A polymorphisms located in the promoter region of the gene in T2DM in the Indian population with bioinformatics analysis of TNF-α protein networking with an aim to find new target sites for the treatment of T2DM. Demographics of 100 diabetes patients and 100 healthy volunteers were collected in a structured proforma and 3 ml blood samples were obtained from the study group, after approval of Institutional Ethics Committee of the hospital (IEC). The information on clinical parameters was obtained from medical records. Genomic DNA was extracted; PCR-RFLP was performed using primers specific to detect the presence of SNPs. Various bioinformatics tools such as STRING software were used to determine its network with other associated genes. The PCR-RFLP studies showed that among the -238G/A types the GG genotype was 87%, GA genotype was 12% and AA genotype was 1%. Almost a similar pattern of results was obtained with -308G/A polymorphism. The results obtained were evaluated statistically to determine the significance. By constructing TNF-α protein interaction network we could analyze ontology and hubness of the network to identify the networking of this gene which may influence the functioning of other genes in promoting T2DM. We could identify new targets in T2DM which may function in association with . Through hub analysis of TNF-α protein network we have identified three novel proteins RIPK1, BIRC2 and BIRC3 which may contribute to mediated T2DM pathogenesis. In conclusion, our study indicated that some of the genotypes of -308G/A, -238G/A were not significantly associated to type 2 diabetes mellitus, but -308G/A polymorphism was reported to be a potent risk factor for diabetes in higher age (>45) groups. Also, the novel hub proteins may serve as new targets against T2DM pathogenesis.
多篇报告记录了肿瘤坏死因子α（TNF-α）和脂质代谢在急性炎症背景下作为肥胖相关胰岛素抵抗的致病因素以及2型糖尿病（T2DM）致病参数之一的作用。我们的目的是通过对TNF-α蛋白网络进行生物信息学分析，研究印度人群中T2DM患者TNF-α基因启动子区域-308G/A和-238G/A多态性之间的关联，以寻找治疗T2DM的新靶点。在医院机构伦理委员会（IEC）批准后，采用结构化表格收集了100例糖尿病患者和100名健康志愿者的人口统计学信息，并从研究组采集了3毫升血液样本。临床参数信息从病历中获取。提取基因组DNA；使用特异性引物进行PCR-RFLP以检测单核苷酸多态性（SNP）的存在。使用诸如STRING软件等各种生物信息学工具来确定其与其他相关基因的网络关系。PCR-RFLP研究表明，在-238G/A类型中，GG基因型为87%，GA基因型为12%，AA基因型为1%。-308G/A多态性也获得了几乎相似的结果模式。对所得结果进行统计学评估以确定其显著性。通过构建TNF-α蛋白相互作用网络，我们可以分析该网络的本体和中心性，以识别该基因的网络关系，这可能会影响其他基因在促进T2DM中的功能。我们可以识别出T2DM中可能与TNF-α协同发挥作用的新靶点。通过对TNF-α蛋白网络的中心性分析，我们确定了三种新蛋白RIPK1、BIRC2和BIRC3，它们可能参与介导T2DM发病机制。总之，我们的研究表明，-308G/A、-238G/A的某些基因型与2型糖尿病无显著关联，但据报道-308G/A多态性是年龄较大（>45岁）人群患糖尿病的一个潜在危险因素。此外，这些新的中心蛋白可能成为对抗T2DM发病机制的新靶点。
