Tumor necrosis factor alpha (TNFa) is an inflammatory cytokine that is involved in the pathogenesis of various inflammatory disorders including rheumatoid arthritis. TNF-alpha receptor I (TNFR1a) is one of the receptors TNFa binds with for its activation. Any variation in this receptor might affect the role of TNFa in successive events. Amino acid residue substitutions might happen in TNFR1a through non-synonymous single nucleotide polymorphisms (nsSNPs) which may alter the functioning of TNFa, hence, identifying any such substitutions is of paramount significance. In this study, six nsSNPs at five different evolutionary conserved regions are predicted to be detrimental to the structure and/or function of TNFR1a by using numerous computational tools. Their 3D models are also proposed in this study. Besides, they were found to reduce the stability and affect the molecular mechanisms of this protein. Two contrasting possibilities might happen because of these substitutions. One, they might reduce the production of TNFa which is overexpressed in inflammatory diseases, hence can play therapeutic role in such diseases. Second, they might possibly hinder the apoptosis to occur which can effectuate the uncontrolled division of cells, hence can be pathogenic in diseases like cancer. Further investigations on these nsSNPs using animal models and at cellular level will open doors to understand the underlying mechanisms behind various diseases.

肿瘤坏死因子α ( TNFa ) 是一种炎症细胞因子，参与包括类风湿性关节炎在内的多种炎症性疾病的发病机制。TNF -α 受体 I ( TNFR1a ) 是TNFa结合并激活的受体之一。该受体的任何变异都可能影响TNFa在连续事件中的作用。TNFR1a中可能通过非同义单核苷酸多态性 (nsSNP) 发生氨基酸残基替换，这可能会改变TNFa的功能，因此，识别任何此类替换至关重要。在这项研究中，通过使用多种计算工具，预测五个不同进化保守区域的 6 个 nsSNP 对TNFR1a的结构和/或功能有害。这项研究还提出了他们的 3D 模型。此外，它们被发现会降低稳定性并影响该蛋白质的分子机制。由于这些替代，可能会出现两种截然不同的可能性。第一，它们可能会减少在炎症性疾病中过度表达的TNFa的产生，因此可以在此类疾病中发挥治疗作用。其次，它们可能会阻碍细胞凋亡的发生，从而导致细胞分裂失控，因此可能导致癌症等疾病。使用动物模型和细胞水平对这些 nsSNP 进行进一步研究将为了解各种疾病背后的潜在机制打开大门。