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

Introduction Although 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. Methods Two genetic... Full description

Journal Title: Critical Care March 5, 2015, Vol.19(1)
Main Author: Cui, Lili
Other Authors: Gao, Yan , Xie, Yuliu , Wang, Yan , Cai, Yujie , Shao, Xin , Ma, Xiaotang , LI, You , Ma, Guoda , Liu, Gen , Cheng, Wanwen , Liu, Yu , Liu, Tingting , Pan, Qunwen , Tao, Hua , Liu, Zhou , Zhao, Bin , Shao, Yiming , Li, Keshen
Format: Electronic Article Electronic Article
Language: English
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ID: ISSN: 1364-8535 ; DOI: 10.1186/s13054-015-0796-x
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recordid: gale_ofa541584945
title: An ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis
format: Article
creator:
  • Cui, Lili
  • Gao, Yan
  • Xie, Yuliu
  • Wang, Yan
  • Cai, Yujie
  • Shao, Xin
  • Ma, Xiaotang
  • LI, You
  • Ma, Guoda
  • Liu, Gen
  • Cheng, Wanwen
  • Liu, Yu
  • Liu, Tingting
  • Pan, Qunwen
  • Tao, Hua
  • Liu, Zhou
  • Zhao, Bin
  • Shao, Yiming
  • Li, Keshen
subjects:
  • Infection – Genetic Aspects
  • Infection – Risk Factors
  • Infection – Analysis
  • Single Nucleotide Polymorphisms – Analysis
  • Interleukins – Analysis
  • Leukemia – Genetic Aspects
  • Leukemia – Risk Factors
  • Leukemia – Analysis
  • Disease Susceptibility – Genetic Aspects
  • Disease Susceptibility – Risk Factors
  • Disease Susceptibility – Analysis
  • Enzymes – Analysis
  • Enzyme-Linked Immunosorbent Assay – Analysis
  • RNA – Analysis
ispartof: Critical Care, March 5, 2015, Vol.19(1)
description: Introduction Although 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. Methods Two 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-[alpha]), and the pro-inflammatory cytokines IL-1[beta] and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10. Results No 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-[alpha]. 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. Conclusions Our 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.
language: eng
source:
identifier: ISSN: 1364-8535 ; DOI: 10.1186/s13054-015-0796-x
fulltext: fulltext
issn:
  • 1364-8535
  • 13648535
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titleAn ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis
creatorCui, Lili ; Gao, Yan ; Xie, Yuliu ; Wang, Yan ; Cai, Yujie ; Shao, Xin ; Ma, Xiaotang ; LI, You ; Ma, Guoda ; Liu, Gen ; Cheng, Wanwen ; Liu, Yu ; Liu, Tingting ; Pan, Qunwen ; Tao, Hua ; Liu, Zhou ; Zhao, Bin ; Shao, Yiming ; Li, Keshen
ispartofCritical Care, March 5, 2015, Vol.19(1)
identifierISSN: 1364-8535 ; DOI: 10.1186/s13054-015-0796-x
subjectInfection – Genetic Aspects ; Infection – Risk Factors ; Infection – Analysis ; Single Nucleotide Polymorphisms – Analysis ; Interleukins – Analysis ; Leukemia – Genetic Aspects ; Leukemia – Risk Factors ; Leukemia – Analysis ; Disease Susceptibility – Genetic Aspects ; Disease Susceptibility – Risk Factors ; Disease Susceptibility – Analysis ; Enzymes – Analysis ; Enzyme-Linked Immunosorbent Assay – Analysis ; RNA – Analysis
descriptionIntroduction Although 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. Methods Two 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-[alpha]), and the pro-inflammatory cytokines IL-1[beta] and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10. Results No 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-[alpha]. 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. Conclusions Our 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.
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titleAn ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis.
descriptionIntroduction Although 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. Methods Two 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-[alpha]), and the pro-inflammatory cytokines IL-1[beta] and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10. Results No 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-[alpha]. 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. Conclusions Our 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.
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1Infection–Risk factors
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3Single nucleotide polymorphisms–Analysis
4Interleukins–Analysis
5Leukemia–Genetic aspects
6Leukemia–Risk factors
7Leukemia–Analysis
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12Enzyme-linked immunosorbent assay–Analysis
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titleAn ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis.
authorCui, Lili ; Gao, Yan ; Xie, Yuliu ; Wang, Yan ; Cai, Yujie ; Shao, Xin ; Ma, Xiaotang ; LI, You ; Ma, Guoda ; Liu, Gen ; Cheng, Wanwen ; Liu, Yu ; Liu, Tingting ; Pan, Qunwen ; Tao, Hua ; Liu, Zhou ; Zhao, Bin ; Shao, Yiming ; Li, Keshen
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6Leukemia–Risk Factors
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abstractIntroduction Although 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. Methods Two 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-[alpha]), and the pro-inflammatory cytokines IL-1[beta] and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10. Results No 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-[alpha]. 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. Conclusions Our 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.
pubBioMed Central Ltd.
doi10.1186/s13054-015-0796-x
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date2015-03-05