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LBP rs2232618 polymorphism contributes to risk of sepsis after trauma.

ABSTRACT: Background:Previous study revealed that rs2232618 polymorphism (Phe436Leu) within LBP gene is a functional variant and associated with susceptibility of sepsis in traumatic patients. Our aim was to confirm the reported association by enlarging the population sample size and perform a meta-analysis to find additional evidence. Methods:Traumatic patients from Southwest (n?=?1296) and Southeast (n?=?445) of China were enrolled in our study. After genotyping, the relationship between rs2232618 and the risk of sepsis was analyzed. Furthermore, we proceeded with a comprehensive literature search and meta-analysis to determine whether the rs2232618 polymorphism conferred susceptibility to sepsis. Results:Significance correlation was observed between rs2232618 and risk of sepsis in Southwest patients (P?=?0.002 for the dominant model, P?=?0.006 for the recessive model). The association was confirmed in Southeast cohort (P?=?0.005 for the dominant model) and overall combined cohorts (P =?4.5?×?10-4, P?=?0.041 for the dominant and recessive model). Multiple logistical regression analyses suggested that rs2232618 polymorphism was related to higher risk of sepsis (OR?=?1.77, 95% CI?=?1.26-2.48, P?=?0.001 in Southwest patients; OR?=?2.11, 95% CI?=?1.24-3.58, P?=?0.006 in Southeast cohort; OR?=?1.54, 95% CI?=?1.34-2.08, P?=?0.006 in overall cohort). Furthermore, meta-analysis of four studies (including the present study) confirmed that rs2232618 within LBP increased the risk of sepsis (OR?=?1.75, P?

SUBMITTER: Lu HX

PROVIDER: S-EPMC6240187 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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LBP rs2232618 polymorphism contributes to risk of sepsis after trauma.

Lu Hong-Xiang HX Sun Jian-Hui JH Wen Da-Lin DL Du Juan J Zeng Ling L Zhang An-Qiang AQ Jiang Jian-Xin JX

World journal of emergency surgery : WJES 20181116

<h4>Background</h4>Previous study revealed that rs2232618 polymorphism (Phe436Leu) within LBP gene is a functional variant and associated with susceptibility of sepsis in traumatic patients. Our aim was to confirm the reported association by enlarging the population sample size and perform a meta-analysis to find additional evidence.<h4>Methods</h4>Traumatic patients from Southwest (<i>n</i> = 1296) and Southeast (<i>n</i> = 445) of China were enrolled in our study. After genotyping, the relatio ...[more]

PMID: 30479651

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Project description:Formyl peptide receptor 2-lipoxin receptor (FPR2/ALX) modulates the anti-inflammatory response and therefore may be a target for treating sepsis. The purpose of this study was to investigate the association between genetic variants of the FPR2/ALX gene and sepsis after severe trauma as well as to further analyze the functions of sepsis-related genetic polymorphisms.Three tag single-nucleotide polymorphisms (tag SNPs) that captured all common alleles across the FPR2/ALX genomic region were genotyped using pyrosequencing in an initial sample consisting of 275 patients with severe trauma. The rs11666254 polymorphism, which had statistical significance, was genotyped in an additional 371 patients, and logistic regression analysis was performed to determine associations between the FPR2/ALX gene polymorphism and sepsis susceptibility after severe trauma. The messenger RNA (mRNA) and protein levels of FPR2/ALX in the lipopolysaccharide-stimulated white blood cells of trauma patients were determined by performing quantitative polymerase chain reactions and Western blot analysis. Tumor necrosis factor (TNF)-? production was measured by enzyme-linked immunosorbent assay. The effects of the promoter polymorphism rs11666254 on the transcription activity of FPR2/ALX were analyzed using a luciferase reporter assay.Among the three tag SNPs, only the rs11666254 polymorphism was found to be significantly associated with sepsis in trauma patients, and this association persisted after a pooled analysis of all 646 trauma patients, which showed that patients who carried the A allele of rs11666254 had a significantly higher risk of developing sepsis than individuals who carried the G allele. This SNP was also significantly associated with lower FPR2/ALX mRNA and protein expression as well as higher TNF-? production from the peripheral blood leukocyte response to bacterial lipoprotein stimulation. In addition, the rs11666254 polymorphism could significantly decrease the promoter activity of the FPR2/ALX gene.The rs11666254 polymorphism in the FPR2/ALX gene is a functional SNP that increases sepsis susceptibility in patients after traumatic injury.

Project description:BackgroundPatients suffering from major trauma often experience complications such as sepsis. The early recognition of patients at high risk of sepsis after trauma is critical for precision therapy. We aimed to derive and validate a novel predictive score for sepsis risk using electronic medical record (EMR) data following trauma.Materials and methodsClinical and laboratory variables of 684 trauma patients within 24 h after admission were collected, including 411 patients in the training cohort and 273 in the validation cohort. The least absolute shrinkage and selection operator (LASSO) technique was adopted to identify variables contributing to the early prediction of traumatic sepsis. Then, we constructed a traumatic sepsis score (TSS) using a logistic regression model based on the variables selected in the LASSO analysis. Moreover, we evaluated the discrimination and calibration of the TSS using the area under the curve (AUC) and the Hosmer-Lemeshow (H-L) goodness-of-fit test.ResultsBased on the LASSO, seven variables (injury severity score, Glasgow Coma Scale, temperature, heart rate, albumin, international normalized ratio, and C-reaction protein) were selected for construction of the TSS. Our results indicated that the incidence of sepsis after trauma increased with an increasing TSS (P trend = 7.44 × 10-21 for the training cohort and P trend = 1.16 × 10-13 for the validation cohort). The areas under the receiver operating characteristic (ROC) curve of TSS were 0.799 (0.757-0.837) and 0.790 (0.736-0.836) for the training and validation datasets, respectively. The discriminatory power of our model was superior to that of a single variable and the sequential organ failure assessment (SOFA) score (P < 0.001). Moreover, the TSS was well calibrated (P > 0.05).ConclusionsWe developed and validated a novel TSS with good discriminatory power and calibration for the prediction of sepsis risk in trauma patients based on the EMR data.

Project description:Sepsis is an organ dysfunction caused by the dysregulated inflammatory response to infection. Lipopolysaccharide-binding protein (LBP) binds to lipopolysaccharide (LPS) and modulates the inflammatory response. A rare systematic study has been reported to detect the effect of LBP gene during LPS-induced sepsis. Herein, we explored the RNA sequencing technology to profile the transcriptomic changes in liver tissue between LBP-deficient rats and WT rats at multiple time points after LPS administration. We proceeded RNA sequencing of liver tissue to search differentially expressed genes (DEGs) and enriched biological processes and pathways between WT and LBP-deficient groups at 0 h, 6 h, and 24 h. In total, 168, 284, and 307 DEGs were identified at 0 h, 6 h, and 24 h, respectively, including Lrp5, Cyp7a1, Nfkbiz, Sigmar1, Fabp7, and Hao1, which are related to the inflammatory or lipid-related process. Functional enrichment analysis revealed that inflammatory response to LPS mediated by Ifng, Cxcl10, Serpine1, and Lbp was enhanced at 6 h, while lipid-related metabolism associated with C5, Cyp4a1, and Eci1 was enriched at 24 h after LPS administration in the WT samples. The inflammatory process was not found when the LBP gene was knocked out; lipid-related metabolic process and peroxisome proliferator-activated receptor (PPAR) signaling pathway mediated by Dhrs7b and Tysnd1 were significantly activated in LBP-deficient samples. Our study suggested that the invading LPS may interplay with LBP to activate the nuclear factor kappa B (NF-κB) signaling pathway and trigger uncontrolled inflammatory response. However, when inhibiting the activity of NF-κB, lipid-related metabolism would make bacteria removal via the effect on the PPAR signaling pathway in the absence of LBP gene. We also compared the serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels using the biochemistry analyzer and analyzed the expression of high mobility group box 1 (HMGB1) and cleaved-caspase 3 with immunohistochemistry, which further validated our conclusion.

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LBP rs2232618 polymorphism contributes to risk of sepsis after trauma.

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LBP rs2232618 polymorphism contributes to risk of sepsis after trauma.

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