Guo Congcong, Zhang Liju, Nie Lihong, Zhang Na, Xiao Di, Ye Xingguang, Ou Meiling, Liu Yang, Zhang Baohuan, Wang Man, Lin Hansheng, Yang Guang, Jing Chunxia
Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, 510632, China.
Department of Endocrine, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
Mol Cell Endocrinol. 2016 Jul 5;429:114-9. doi: 10.1016/j.mce.2016.04.003. Epub 2016 Apr 8.
Type 2 diabetes mellitus (T2DM) has been linked to a state of low-grade inflammation resulting from abnormalities in the innate immune pathway. MyD88 is an essential adaptor protein for TLR signaling, which is involved in activating NF-κB through IRAK4 and TRAF6. To investigate the effects of the MyD88, IRAK4 and TRAF6 polymorphisms in the susceptibility of T2DM and diabetic vascular complications, eight SNPs were analyzed in 553 T2DM patients and 553 matched healthy controls. Gene-gene interactions and haplotype associations were also evaluated. We found a significant increased risk of T2DM for the AG genotype of rs6853 in MyD88 gene and the CT genotype of rs4251532 in IRAK4 gene. Significant association was also found between rs16928973 in TRAF6 gene and diabetic nephropathy (DN) under the allelic model. Moreover, the TA haplotype in TRAF6 was negatively associated with DN. No significant gene-gene interactions were found. In conclusion, our results indicate that the polymorphisms in TLR-MyD88-NF-κB signaling pathway confer genetic susceptibility to T2DM and DN.
2型糖尿病（T2DM）与先天免疫途径异常导致的低度炎症状态有关。髓样分化因子88（MyD88）是Toll样受体（TLR）信号传导的一种重要衔接蛋白，其通过白细胞介素-1受体相关激酶4（IRAK4）和肿瘤坏死因子受体相关因子6（TRAF6）参与激活核因子κB（NF-κB）。为了研究MyD88、IRAK4和TRAF6基因多态性对T2DM易感性及糖尿病血管并发症的影响，我们在553例T2DM患者和553例匹配的健康对照中分析了8个单核苷酸多态性（SNP）。同时也评估了基因-基因相互作用和单倍型关联。我们发现，MyD88基因中rs6853的AG基因型和IRAK4基因中rs4251532的CT基因型使T2DM风险显著增加。在等位基因模型下，TRAF6基因中的rs16928973与糖尿病肾病（DN）也存在显著关联。此外，TRAF6基因中的TA单倍型与DN呈负相关。未发现显著的基因-基因相互作用。总之，我们的结果表明，TLR-MyD88-NF-κB信号通路中的多态性赋予了T2DM和DN的遗传易感性。
