Genetic Variation in the TNF Gene Is Associated with Susceptibility to Severe Sepsis, but Not with Mortality

<div><h3>Background</h3><p>Tumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of <em>TNF</em> and <em>lymphotoxin-α</em> (<em>LTA</em>) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in <em>TNF</em>, <em>LTA</em>, <em>TNFRSF1A</em> and <em>TNFRSF1B</em> was associated with susceptibility to or death from severe sepsis in Chinese Han population.</p> <h3>Methodology/Principal Findings</h3><p>Ten SNPs in <em>TNF</em>, <em>LTA</em>, <em>TNFRSF1A</em> and <em>TNFRSF1B</em> were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of <em>TNF</em>, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (P_adj = 0.00046, odds ratio (OR)_adj = 1.92) and sepsis patients (P_adj = 0.002, OR_adj = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-α concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) <em>ex vivo</em>, and the association between rs1800629 and TNF-α serum levels in severe sepsis patients. After exposure to LPS, the TNF-α concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-α serum concentrations than those with GG genotype (P_adj = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis.</p> <h3>Conclusions/Significance</h3><p>Our findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population.</p> </div

Demographic and clinical characteristics of the study subjects.

<p>N.A, not applicable; APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment. P¹, sepsis group vs severe sepsis group. P², survivor group vs non-survivor group.</p

Association of TNF-α levels and rs1800629 genotypes in healthy volunteers.

<p>Concentrations of TNF-α in culture supernatants of PBMCs were expressed as the median, interquartile range and extremes. The TNF-α levels were significantly different between individuals with AA+GA and GG genotypes under the LPS-stimulated condition (P = 0.007). However, no significant difference was observed under the unstimulated condition (P = 0.56).</p

Association analysis of SNPs in <i>TNF</i>, <i>LTA</i>, <i>TNFRSF1A</i> and <i>TNFRSF1B</i> between survivors and non-survivors of severe sepsis patients.

<p>SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval. P_adj and OR_adj came from multivariate logistic regression. A P-value of <0.005 (0.05/10) was considered statistically significant after Bonferroni correction. The comparator group was survivors.</p

Characteristics of all tested SNPs in <i>TNF</i>, <i>LTA</i>, <i>TNFRSF1A</i> and <i>TNFRSF1B</i>.

<p>SNP, single nucleotide polymorphism; HWE, Hardy-Weinberg equilibrium; UTR, untranslated region.</p

Association of TNF-α levels and rs1800629 genotypes in severe sepsis patients.

<p>TNF-α serum levels in severe sepsis patients were expressed as the median, interquartile range and extremes. The TNF-α levels were significantly different between individuals with AA+GA and GG genotypes (P = 0.001). The difference remained significant (P_adj = 0.02) after adjustment for age, gender and APACHE II scores in a linear regression model.</p

Table_1_Testosterone and soluble ST2 as mortality predictive biomarkers in male patients with sepsis-induced cardiomyopathy.docx

Sepsis-induced cardiomyopathy (SIC) is characterized by high mortality and poor outcomes. This study aimed to explore the relationship between testosterone and soluble ST2 (sST2) and all-cause mortality in patients with SIC. Clinical data from SIC patients at Renmin Hospital of Wuhan University from January 2021 and March 2023 were reviewed. Serum testosterone and sST2 were measured at admission. Kaplan–Meier analysis and receiver operative characteristic curve (ROC) were used to estimate the predictive values of testosterone and sST2 on 28 days and 90 days mortality of SIC. A total of 327 male subjects with SIC were enrolled in this study. During the 28 days and 90 days follow-up, 87 (26.6%) and 103 deaths (31.5%) occurred, respectively. Kaplan–Meier analysis showed significantly higher 28 days and 90 days survival in patients with higher testosterone and decreased sST2 levels (p < 0.001). Testosterone, sST2, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were significantly associated with 28 days and 90 days mortality (p < 0.05). Partial correlation analysis showed strong positive correlation between testosterone and left ventricular ejection fraction (LVEF) (p < 0.001), and negative correlation between testosterone and sST2 (p < 0.001), high-sensitivity troponin I (hs-TnI) levels (p < 0.001) and smoke history (p < 0.01). The concentrations of sST2 were positively related with E/e′ ratio (p < 0.001), and negatively correlated with TAPSE (p < 0.001). The combination of testosterone and sST2 enhanced the prediction of both 28 days [area under the ROC curve (AUC), 0.805] and 90 days mortality (AUC, 0.833). Early serum testosterone and sST2 levels could predict mortality of SIC independently and jointly. Further research is needed to determine the utility of biochemical markers in identifying high-risk patients with SIC.</p

A follow-up study on the recovery and reinfection of Omicron COVID-19 patients in Shanghai, China

Limited follow-up data is available on the recovery of Omicron COVID-19 patients after acute illness. It is also critical to understand persistence of neutralizing antibody (NAb) and of T-cell mediated immunity and the role of hybrid immunity in preventing SARS-CoV-2 reinfection. This prospective cohort study included Omicron COVID-19 individuals from April to June 2022 in Shanghai, China, during a large epidemic caused by the Omicron BA.2 variant. A total of 8945 patients from three medical centers were included in the follow up program from November, 2022 to February, 2023. Of 6412 individuals enrolled for the long COVID analysis, 605 (9.4%) individuals experienced at least one sequelae, mainly had fatigue and mental symptoms specific to Omicron BA.2 infection compared with other common respiratory tract infections. During the second-visit, 548 (12.1%) cases of Omicron reinfection were identified. Hybrid immunity with full and booster vaccination had reduced risk of SARS-CoV-2 reinfection by 0.29-fold (95% CI: 0.63 - 0.81) and 0.23-fold (95% CI: 0.68 - 0.87), respectively. For 469 participants willing to the hospital during the first visit, those who received full (72 [IQR, 36 - 156]) or booster (64 [IQR, 28 - 132]) vaccination had significantly higher neutralizing antibody titers than those with incomplete vaccination (36 [IQR, 16 - 79]). Moreover, non-reinfection cases had higher neutralizing antibody titers (64 [IQR, 28 - 152]) compared to reinfection cases (32 [IQR, 20 - 69]).</p