Shao Yiming, He Junbing, Chen Feng, Cai Yujie, Zhao Jianghao, Lin Yao, Yin Zihan, Tao Hua, Shao Xin, Huang Pengru, Yin Mingkang, Zhang Wenying, Liu Zhou, Cui Lili
The Intensive Care Unit, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, PR China.
Cell Physiol Biochem. 2016;39(4):1247-61. doi: 10.1159/000447830. Epub 2016 Sep 8.
A disintegrin and metalloproteinase 17 (ADAM17) has been confirmed to play a significant role in the pathogenesis of sepsis. However, little is known about the clinical relevance of ADAM17 polymorphisms to sepsis onset and development.
This study analyzed the associations of five ADAM17 promoter polymorphisms (rs55790676, rs12692386, rs11684747, rs1524668 and rs11689958) with sepsis (370 sepsis cases and 400 controls). Genotyping was performed using pyrosequencing and polymerase chain reaction-length polymorphism method. The ADAM17 expression was measured using the real-time PCR method and the concentrations of related cytokines were detected using enzyme-linked immunosorbent assay.
No associations were observed between these polymorphisms and sepsis susceptibility, while the rs12692386GA/GG genotypes were overrepresented among the patients with severe sepsis (P=0.002) or septic shock (P=0.0147) compared to those with sepsis subtype, suggesting a susceptible role of rs12692386A>G in the progression of sepsis. Moreover, ADAM17 expression was increased in the sepsis patients with the rs12692386GA/GG genotypes, accompanied by up-regulation of expression of the ADAM17 substrates (TNF-α, IL-6R and CX3CL1) and pro-inflammatory cytokines (IL-1β and IL-6).
The present study has provided potentially valuable clinical evidence that the ADAM17 rs12692386 polymorphism is a functional variant that might be used as a relevant risk estimate for the progression of sepsis.
解整合素金属蛋白酶17（ADAM17）已被证实在脓毒症发病机制中起重要作用。然而，关于ADAM17基因多态性与脓毒症发生发展的临床相关性知之甚少。
本研究分析了5个ADAM17启动子多态性（rs55790676、rs12692386、rs11684747、rs1524668和rs11689958）与脓毒症（370例脓毒症病例和400例对照）的相关性。采用焦磷酸测序和聚合酶链反应-长度多态性方法进行基因分型。采用实时PCR法检测ADAM17表达，采用酶联免疫吸附测定法检测相关细胞因子浓度。
未观察到这些多态性与脓毒症易感性之间存在关联，而与脓毒症亚型患者相比，rs12692386GA/GG基因型在严重脓毒症（P=0.002）或感染性休克（P=0.0147）患者中比例过高，提示rs12692386A>G在脓毒症进展中起易感作用。此外，rs'12692386GA/GG基因型脓毒症患者的ADAM17表达增加，同时伴有ADAM17底物（TNF-α、IL-6R和CX3CL1）和促炎细胞因子（IL-1β和IL-6）表达上调。
本研究提供了潜在有价值的临床证据，即ADAM17 rs12692386多态性是一个功能性变异，可能用作脓毒症进展的相关风险评估指标。
