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A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis.

ABSTRACT: Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (THBD). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis. Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis. Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (-1920^*C/G; rs2239562) [odds ratio [OR] 2.709 (1.067-6.877), P = 0.033 and OR 1.768 (1.060-2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [OR 1.593 (1.086-2.338), P = 0.017]. Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis.

SUBMITTER: Watanabe E

PROVIDER: S-EPMC8785550 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AbstractTo investigate the relationship between thrombomodulin (THBD) gene single nucleotide polymorphisms (SNPs) and susceptibility to sepsis and the occurrence and prognosis of acute kidney injury (AKI) in sepsis patients.The genotypes of THBD gene rs1962, rs3176123, and rs1042580 in 178 sepsis patients with AKI, 243 sepsis patients without AKI (No AKI), and 103 healthy controls were analyzed by direct sequencing. Enzyme-linked immunosorbent assay (ELISA) was used to detect the plasma THBD protein levels. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of plasma THBD levels in sepsis, AKI, and death of sepsis patients.The C allele carriers of THBD gene rs1962 were more likely to develop AKI and sepsis than the T allele carriers (OR = 1.61, 95% CI: 1.18-2.19, P < .01; OR = 2.16, 95% CI: 1.42-3.29, P < .01). The rs3176123 G allele was associated with an increased risk of AKI in sepsis patients (OR = 1.41, 95% CI: 1.06-1.88, P = .02), the G allele had a significant association with a higher risk of sepsis susceptibility (OR = 1.91, 95% CI: 1.33-2.75, P < .01). Sepsis patients of rs1042580 C allele had a lower risk of AKI than those of T allele (OR = 0.58, 95% CI: 0.37-0.91, P = .02), the C allele was related to a reduced risk of sepsis susceptibility (OR = 0.38, 95% CI: 0.26-0.55, P < .01). The THBD gene rs1962, rs3176123, and rs1042580 TGT haplotype was linked to higher risk of AKI in patients with sepsis (OR = 1.96, 95%CI: 1.14-3.38, P = .02). Sepsis patients with the THBD gene rs1962 TC + CC genotype had a higher risk of death than those with TT genotype (OR = 10.93, 95%CI: 5.05-26.96, P < .01), but there was no significant difference in the risk of death in sepsis patients with different genotypes at rs3176123 and rs1042580 (P > .05).The THBD gene rs1962, rs3176123, and rs1042580 SNPs are significantly associated with sepsis susceptibility and the risk of AKI. The rs1962 SNP is related to the risk of death in sepsis patients.

Project description: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.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-?), and the pro-inflammatory cytokines IL-1? and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10.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-?. 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.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.

Project description:To investigate the association between the susceptibility to cervical cancer and the single nucleotide polymorphisms of 5 tumor necrosis factor-α promoter genes (rs361525, rs1800629, rs1800750, rs1799964, and rs673) in Chinese women. A total of 946 peripheral blood samples were collected from women of Han Ethnicity in Shandong province. Of them, 452 were diagnosed with cervical squamous cell carcinomas. The study also included a control group of 494 healthy women. The targeted single nucleotide polymorphisms were analyzed by TaqMan probe method. (1) The rate of high-risk subtype human papillomavirus infection in exfoliated cervical epithelial cells was significantly higher in patients with cervical cancer than the control group (91.4% vs 10.3%, P < .01). The rate of human papillomavirus infection was lower in patients with carcinoma in situ than those with invasive carcinoma (77.9% vs 95.4%, P < .01). (2) There was a significant difference for rs361525 genotype (CC/CT/TT) between the control, carcinoma in situ, and invasive carcinoma groups ( P < .001). Both rs1800629 and rs1799964 genotypes (both GG/GA/AA) were also different between these groups ( P < .001 and P < .001). (3) The allele frequencies of rs361525, rs1800629, and rs1799964 were significantly correlated with the diagnosis of cervical cancer. The frequency of T allele in rs361525 was significantly higher for cervical cancer group (10.8%) than control group (3.8%; odds ratio = 3.04, 95% confidence interval = 1.76-5.25, P < .01). The frequency of A allele in rs1800629 was significantly higher for cervical cancer (29.9%) than control group (14.2%; odds ratio = 2.58, 95% confidence interval = 1.87-3.56, P < .01). The frequency of A allele in rs1799964 was also higher for cervical cancer group (38.3%) than control group (16.4%; odds ratio = 1.43, 95% confidence interval = 1.07-1.91, P < .05). The rs361525, rs1800629, and rs17999645 were significantly correlated with the diagnosis of cervical cancer.

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A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis.

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