An ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis

Abstract

IntroductionAlthough genetic variants of the A disintegrin and metalloproteinase 10 (ADAM10) gene have been shown to be associated with susceptibility to several inflammatory-related diseases, to date little is known about the clinical relationship in the development of sepsis.MethodsTwo genetic variants in the promoter of ADAM10 were selected to analyze the potential association with the risk of sepsis. A total of 440 sepsis patients and 450 matched healthy individuals in two independent Chinese Han population were enrolled. Pyrosequencing and polymerase chain reaction-length polymorphism was used to determine the genotypes of the rs514049 and rs653765. A real-time qPCR method was used to detect the mRNA level of ADAM10. Enzyme-linked immunosorbent assay was used to measure the expression levels of substrates CX3CL1, interleukin (IL)-6R, tumor necrosis factor alpha (TNF-α), and the pro-inflammatory cytokines IL-1β and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10.ResultsNo statistically significant differences between sepsis cases and controls in the genotype or allele frequencies were observed, suggesting that ADAM10 single nucleotide polymorphisms (SNPs) may not be risk factors for the occurrence of sepsis. A significant difference in the genotype and allele frequencies of the rs653765 SNP between patients with sepsis subtype and severe sepsis (P = 0.0014) or severe sepsis/sepsis shock (P = 0.0037) were observed. Moreover, the rs653765 CC genotype in severe sepsis showed a higher ADAM10 level compared to healthy groups, and the rs653765 CC polymorphism had a strong impact on the production of the ADAM10 substrates CX3CL1, IL-6R and TNF-α. Furthermore, the functional assay showed that ADAM10 C-A haplotype carriers exhibited significantly higher reporter activity compared with the T-A carriers and T-C carriers in human acute monocytic leukemia cell line.ConclusionsOur data initially indicated the ADAM10 rs653765 polymorphism was associated with the development of severe sepsis; the risk CC genotype could functionally affect the expression level of ADAM10 mRNA and was accompanied by the up-regulation of its substrates. Thus, ADAM10 might be clinically important and play a critical role in the pathogenesis of the development of sepsis, with potentially important therapeutic implications.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0796-x) contains supplementary material, which is available to authorized users.

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

“…Indeed, there is literature regarding the putative AT receptor ADAM10. Analysis of ADAM10 polymorphisms in human sepsis revealed that the C allele of rs653765 ADAM10 promoter conferred susceptibility to the most severe septic episodes due to increased ADAM10 levels (Cui et al, 2015). In addition, we observed that AT and S. aureus culture supernatant induced rapid human platelet aggregation that was inhibited by MEDI4893*.…”

Impact of ADAM10 gene polymorphisms on hepatocellular carcinoma development and clinical characteristics

“…Moreover, the rs653765 polymorphism may be a functional SNP because the rs653765 C > T polymorphism is located one base downstream of the potential site for the myc-associated zinc finger protein (MAZ) transcription factor 16. The ADAM10 rs653765 polymorphism was also associated with the development of severe sepsis 17; however, the risk CC genotype was suggested to have functionally affected the expression level of ADAM10 mRNA, which was accompanied by the upregulation of its substrates 17, compared with the “GA + AA” genotype in HCC being associated with a higher risk of distant metastasis in the present study (Table 4). Although the functions and detailed mechanisms of ADAM10 rs514049 remain uncertain and controversial, rs514049 and rs653765 are involved in HCC disease progression and metastasis, and rs653765 may play a more essential role in regulating ADAM10 expression in HCC and other diseases.…”

Association Study Between Promoter Polymorphisms of ADAM17 and Progression of Sepsis

“…To date, numerous of studies have demonstrated that several functional genetic variations in the genes encoding RAGE, ADAM10 and TNF-α may influence the risk and development of sepsis [32][33][34][35]. However, to the best of our knowledge, the genetic variations of ADAM17 have not been determined in patients with sepsis, adequately.…”