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The Pro12Ala Polymorphism of PPAR-γ Gene Is Associated with Sepsis Disease Severity and Outcome in Chinese Han Population
PPAR Research
Abstract and Figures
Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR) method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P = 0.622 for genotype; P = 0.629 for allele). However, stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P = 0.014 for allele and P = 0.012, for genotype). Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P = 0.002). In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P < 0.001). Thus, genetic polymorphism is thought to play a role in the development and outcome of sepsis.
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... However, investigations of the relation of PPARγ single-nucleotide polymorphisms (SNPs) with sepsis are rare and each concentrated on only one or a small number of SNPs. 18,19 Hence, some SNPs of the PPARγ gene have yet to be investigated for their possible influence on the susceptibility to sepsis or the prognosis of this condition. Therefore, the aim of this study was to analyze the association between common SNPs in the PPARγ gene (a total of 13 SNPs) and the susceptibility to and clinical outcome of sepsis in a North China Han population. ...
... 26 However, patients carrying the G allele had lower disease severity and a better prognosis than those with the C allele. 18 The reasons underlying the apparent inconsistency between our study and that of Ma et al 18 others ,have suggested no effect. 33 A recent meta-analysis 34 PPARγ and a target gene is not required for this anti-inflammatory function. ...
... 26 However, patients carrying the G allele had lower disease severity and a better prognosis than those with the C allele. 18 The reasons underlying the apparent inconsistency between our study and that of Ma et al 18 others ,have suggested no effect. 33 A recent meta-analysis 34 PPARγ and a target gene is not required for this anti-inflammatory function. ...
Background:
Peroxisome proliferator-activated receptor-γ (PPARγ) is a regulator of inflammation. This study aimed to explore associations between PPARγ gene single-nucleotide polymorphisms (SNPs) and susceptibility to and clinical outcome of sepsis in the North China Han population.
Methods:
This study included 303 patients with sepsis and 303 controls. We conducted genetic typing for 13 common PPARγ gene SNPs (improved multiplex ligation detection reaction), linkage disequilibrium mapping, and haplotype inference. Associations between SNP genotypes/haplotypes and sepsis susceptibility and outcome (septic shock, organ dysfunction, or death) were assessed using unconditional logistic regression analysis.
Results:
For rs2972164, patients with genotypes CT/CT+TT had higher risk of sepsis than genotype CC (odds ratio [95% CI]: 1.74 [1.05-2.86], P = .03 and 1.72 [1.06-2.80], P = .026, respectively); the T allele was associated with increased sepsis risk compared with the C allele (1.64 [1.04-2.58], P = .033). For rs1801282, genotypes CG/CG+GG had lower risk of sepsis than genotype CC (0.55 [0.33-0.92], P = .024 and 0.57 [0.35-0.95], P = .03, respectively); the G allele was associated with decreased sepsis risk compared with the C allele (0.62 [0.39-1.01], P = .055). For rs4135275, genotypes AG/AG+GG had higher risk of severe organ dysfunction (multiple organ dysfunction syndrome score >8) than genotype AA (2.66 [1.16-6.09], P = .038 and 2.21 [1.00-4.85], P = .042, respectively). Haplotype TAT (rs2972164, rs4684846, and rs17036188) was associated with increased sepsis risk (1.66 [1.03-2.67], P = .038).
Conclusions:
No mutation was correlated with septic shock or death. PPARγ gene polymorphisms may play a role in the occurrence and progression of sepsis in the North China Han population.
... The incidence of mutant allele in both homozygosity (GG) and in heterozygosity (GC) together was 71.67%. On other hand, Ma et al. [11] found insignificant differences in the genotype distribution of the PPAR-c Pro12Ala variant between the sepsis patients and healthy controls in the Chinese Han population. Furthermore, they found that the frequency of the mutant allele (G) in homozygosity alone (GG) (Pro12Pro) was much higher (96.59%) than current study. ...
... In this study, the most prevalent genotype among our patients was homozygote (GG) for polymorphic locus (coding for Alanine/ Alanine). This is in contrast to Ma et al., [11] who reported that the frequency of (CC) genotype was the most prevalent (93.18%) followed by GC (6.82%) in their patients group. ...
... This may suggest high risk for occurrence of neonatal sepsis with PPAR-c G allele. Stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls [11]. ...
Background
Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a ligand-dependent transcription factor involved in inflammatory process. PPAR-γ gene was mentioned as having a modulating role in the pathological status of sepsis.
The present study aimed to make a correlation between The Pro12Ala polymorphism in PPAR-γ gene and occurrence of neonatal sepsis and its severity among a sample of Egyptian neonates suffering sepsis.
Subjects and methods
This case-control study included 30 neonates (11 females and19 males) newly admitted with neonatal sepsis at the intensive care unit (NICU) (mean age 10.3 days ± 6.23). The control group included 50 age and sex matched neonates (23 females and 27 males) (mean age 10.20 days ± 5.36 days). All the neonates (preterm and full term) included were with clinical signs and laboratory data consistent with neonatal sepsis. Genotyping for PPARγ gene region harboring the Pro12Ala variant locus were carried out using Tetra ARMS technique.
Results
About 56.7% of the patients group was homozygote (GG) for polymorphic locus (coding for Alanine/Alanine) while 30% was heterozygote for polymorphic locus (CG) (coding for Proline/Alanine) and up to 13.3% was homozygote for the polymorphic locus (CC) (coding for Proline/Proline). Compared to the control group where homozygotes for CC were the most prevalent (90%) and the CG were 10% with absence of GG genotypes. There was a strong statistical significant difference between patients and the normal control group as regards prevalence of PPAR-γ gene polymorphism in occurrence of neonatal sepsis and its severity. Also, there were strong relation between genotype GG and low birth weight, neonatal fever, prematurity and depressed neonatal reflexes.
Conclusion
PPAR-γ gene has been suggested to be a candidate gene for neonatal sepsis. Therefore, Pro12Ala polymorphism might be useful in predicting the risk factor of neonatal sepsis and its severity.
... In recent years, although the methods of treatment have been frequently updated and refined, sepsis and septic shock have remained the most common causes of death in intensive care units (ICUs) [25]. Hence, many studies have focused on finding treatment targets for sepsis. ...
Background:
Genetic variant is one of the causes of sepsis patients' mortality. Now, many studies have identified several SNPs related to sepsis. However, none of these studies were identified in a genome-wide way. We aimed to detect genetic polymorphisms of sepsis patients.
Methods:
The blood samples of eight normal controls and ten sepsis patients were collected for whole exome sequencing. Then, Single Nucleotide Polymorphisms (SNPs) were selected according to quality score and number of sepsis patients who had this variants. Synonymous mutations were removed. Genes including these remaining variants were used for functional analyses. After analyses, the remaining SNPs and indels were validated in 149 normal controls and 156 sepsis patients. Finally, serum levels of proteins coded by genes including these SNPs were evaluated.
Results:
After whole exome sequencing, 97 SNPs and one indel site were left. Then, functional screening was performed. Only seven SNPs were used for further validation. As a result, the rs2721068 in dominant model and rs17446614 in recessive model were associated with sepsis, and the ORs of these two SNPs were 3.24 (95%CI, 1.25, 8.44) and 0.47 (0.026, 0.88), respectively. These two SNPs were both located in Forkhead box O1 (FOXO1) gene. For rs2721068 (T/T, T/C-C/C) and rs17446614 (A/A-A/G, G/G), serum levels of foxo1 in sepsis patients were both significantly lower in normal controls.
Conclusions:
We firstly reported that the rs2721068 and rs17446614 were correlated to genetic predisposition to sepsis.
... Nonsynonymous PPARG genetic variants were associated with altered outcomes in both sepsis and CVD (Table 1). [20][21][22] Pattern Recognition Receptors CD14: CD14 is a glycosylphosphatidylinositol-anchored membrane glycoprotein constitutively expressed on monocytes/macrophages and neutrophils as part of a coreceptor within the MD2-Toll-like receptor 4 (TLR4) complex and binds to lipopolysaccharide and other microbial and nonmicrobial ligands. Soluble CD14 (sCD14) binds and inactivates lipopolysaccharide. ...
Genetic variants are associated with altered clinical outcome of patients with sepsis and cardiovascular diseases. Common gene signaling pathways may be involved in the pathophysiology of these diseases. A better understanding of genetic commonality among these diseases may enable the discovery of important genes, signaling pathways, and therapeutic targets for these diseases. We investigated the common genetic factors by a systematic search of the literature. Twenty-four genes (ADRB2, CD14, FGB, FV, HMOX1, IL1B, IL1RN, IL6, IL10, IL17A, IRAK1, MASP2, MBL, MIR608, MIF, NOD2, PCSK9, PPARG, PROC, SERPINE1, SOD2, SVEP1, TF, TIRAP, TLR1) were extracted as reported genetic variations associated with altered outcome of both sepsis and cardiovascular diseases. Of these genes, the adverse allele (or combinations) was same in nine (ADRB2, FV, HMOX1, IL6, MBL, MIF, NOD2, PCSK9, SERPINE1), and the effect appears to be in the same direction in both sepsis and cardiovascular disease. Shared gene signaling pathways suggest that these are true biological results and could point to overlapping drug targets in sepsis and cardiovascular disease.
... Therefore, it would be an important way to investigate the roles of PPARs in the development of sepsis and MODS by elucidating the clinical association between SNPs in PPARs genes and patients' different responses to trauma. Although a previous study has assessed the association between the Pro12Ala polymorphism of PPARγ and sepsis mortality [21], little was known about the clinical relevance of other SNPs in PPAR family genes in relation to the development of sepsis and MODS in trauma patients. ...
Background:
Peroxisome proliferator-activated receptors (PPARs) play important roles in the development of inflammatory diseases and sepsis. Recently, genetic variants of PPARs genes have been widely studied in some inflammatory diseases. However, the association between PPAR family of genes polymorphisms and sepsis risk in trauma patients was little known.
Methods:
SNPs were selected from the PPARs genes through constructing haplotype blocks and genotyped by the improved multiplex ligation detection reaction (iMLDR) method. The association between the selected SNPs and the risk of sepsis and multiple organ dysfunction (MOD) scores was evaluated in 734 trauma patients. In addition, tumor necrosis factor α (TNFα) production of peripheral blood leukocytes was also analyzed after lipopolysaccharide (LPS) stimulation.
Results:
Our results revealed that there were significant associations between the rs10865710 polymorphism and the risk of sepsis and MOD scores in Chinese Han trauma patients. Further, we found that the level of TNFα production was higher in patients with the rs10865710 G allele compared to those with the variant C allele.
Conclusions:
The rs10865710 polymorphism in the PPARγ gene might be used to assess the risk of sepsis and multiple organ dysfunction syndrome (MODS) in trauma patients.
Conflicting results have been reported on the association of the Pro12Ala polymorphism of the PPARγ2 gene with the risk of type 2 diabetes or obesity.
A total of 3146 subjects with 1145 cases of type 2 diabetes and 2001 healthy controls were included in the study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using an allelic discrimination assay-by-design TaqMan method. Overall, the Ala allele frequency was 5.6% in control subjects and 3.9% in diabetes subjects (P = 0.023). We found a statistically significant association of carriers of the Ala allele with greater homoeostasis model assessment of beta cell function index in all subjects (P = 0.046). After controlling for confounders, carriers of the Ala allele had a decreased risk of diabetes compared with noncarriers [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49-0.83; P = 0.001]. A beneficial effect of the Ala allele was also observed for obesity (OR 0.64, 95% CI 0.42-0.96; P = 0.030).
Our results suggested that the presence of the Ala allele may contribute to improved insulin secretory capacity and may confer protection from type 2 diabetes and obesity in the Chinese population.
The polymorphism Pro12Ala in peroxisome proliferator-activated receptorgamma2 gene (PPARgamma2) has been reported to be associated with diabetic nephropathy (DN) in some studies, though the results remain inconclusive. To explore this relationship between PPARgamma2 Pro12Ala polymorphism and the susceptibility for DN, a cumulative meta-analys is was performed in this study.
PubMed, Medline, Embase and Web of Science databases have been systematically searched to identify relevant studies. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated.
18 studies were included in this meta-analysis, involving 3,361 cases and 5,815 controls. The PPARgamma2 Ala12 allele was significantly associated with decreased risk of DN based on dominant model (OR=0.778; 95%CI=0.618-0.981; Pheterogeneity=0.008; P=0.034). In the stratified analysis by ethnicity, significantly decreased risks were found among Caucasians for dominant model (OR=0.674; 95%CI=0.500-0.909; Pheterogeneity=0.079; P=0.010), while there was no significant association was found in Asians.
The results from the present meta-analysis indicated that the Pro12Ala polymorphism in PPARgamma2 gene is not a risk factor for DN in type 2 diabetes (T2D). Further large and well-designed studies are needed to confirm this conclusion. Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7491348341027320.
Bacterial endotoxin (LPS)-mediated sepsis involves severe, dysregulated inflammation that injures the lungs and other organs, often fatally. Vascular endothelial cells are both key mediators and targets of LPS-induced inflammatory responses. The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) exerts anti-inflammatory actions in various cells, but it is unknown whether it modulates inflammation through actions within endothelial cells. To determine whether PPARγ acts within endothelial cells to diminish endotoxemic lung inflammation and injury, we measured inflammatory responses and mediators in mice with endothelial-targeted deletion of PPARγ. Endothelial cell PPARγ (ePPARγ) knockout exacerbated LPS-induced pulmonary inflammation and injury as shown by several measures, including infiltration of inflammatory cells, edema, and production of reactive oxygen species and proinflammatory cytokines, along with upregulation of the LPS receptor TLR4 in lung tissue and increased activation of its downstream signaling pathways. In isolated LPS-stimulated endothelial cells in vitro, absence of PPARγ enhanced the production of numerous inflammatory markers. We hypothesized that the observed in vivo activity of the ligand-activated ePPARγ may arise, in part, from nitrated fatty acids (NFAs), a novel class of endogenous PPARγ ligands. Supporting this idea, we found that treating isolated endothelial cells with physiologically relevant concentrations of the endogenous NFA 10-nitro-oleate reduced LPS-induced expression of a wide range of inflammatory markers in the presence of PPARγ, but not in its absence, and also inhibited neutrophil mobility in a PPARγ-dependent manner. Our results demonstrate a key protective role of ePPARγ against endotoxemic injury and a potential ePPARγ-mediated anti-inflammatory role for NFAs.
Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, has been implicated playing a role in the development of inflammatory bowel disease (IBD). However, previous studies evaluating the association between the PPARγ2 Pro12Ala polymorphism and IBD are inconsistent. We performed a meta-analysis to determine whether the PPARγ2 Pro12Ala mutation was associated with the presence of IBD.
Electronic databases were searched for case-control studies evaluating the association between the Pro12Ala mutation and the presence of IBD. Effects were summarized with the methods recommended by the Cochrane Collaboration. A total of 7 studies including 1002 ulcerative colitis (UC) cases, 1090 Crohǹs disease (CD) cases and 1983 controls were involved in this meta-analysis. In the overall analysis, no significant association of this polymorphism with UC or CD was found. In the subgroup analyses in different populations, AlaAla genotype seemed to protect the European Caucasian population against the development of CD (Pro vs Ala: OR = 1.135, 95%CI = 0.951-1.354, P = 0.162, Bon = 1.000; ProPro vs ProAla: OR = 1.042, 95%CI = 0.852-1.273, P = 0.690, Bon = 1.000; ProPro vs AlaAla: OR = 2.379, 95%CI = 1.110-5.100, P = 0.026, Bon = 0.156; ProAla vs AlaAla: OR = 2.315, 95%CI = 1.064-5.037, P = 0.034, Bon = 0.204; Pro homozygotes vs Ala positives: OR = 1.094, 95%CI = 0.899-1.330, P = 0.371, Bon = 1.000; Pro positives vs Ala homozygotes: OR = 2.360, 95%CI = 1.103-5.053, P = 0.027, Bon = 0.162; heterozygotes vs all homozygotes: OR = 0.976, 95%CI = 0.799-1.192, P = 0.809, Bon = 1.000). There was no significant association of this polymorphism with UC or CD in the East Asian population and the Turkish population.
AlaAla genotype may be a protective factor in the European Caucasian population against the development of CD in a recessive way.
The pathogenesis of sepsis and its progression to multiple organ dysfunction syndrome and septic shock have been the subject of investigations for nearly half a century. Controversies still exist with regard to understanding the molecular pathophysiology of sepsis in relation to the complex roles played by reactive oxygen species, nitric oxide, complements and cytokines. In the present review we categorise the key turning points in sepsis development and outline the most probable sequence of events leading to cellular dysfunction and organ failure under septic conditions. We have applied an integrative approach in order to fuse current state-of-the-art knowledge about redox processes involving hydrogen peroxide, nitric oxide, superoxide, peroxynitrite and hydroxyl radical, which lead to mitochondrial respiratory dysfunction. Finally, from this point of view, the potential of redox therapy targeting sepsis is discussed.
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
To examine the effects of pioglitazone, peroxisome proliferator-activated receptor-gamma (PPAR-γ), on mortality and omental adipocyte function in mice with cecal ligation and puncture (CLP).
Male mice were assigned to receive (1) vehicle/sham-operation, (2) pioglitazone/CLP, or (3) vehicle/CLP. Pioglitazone was injected intraperitoneally for 7 d before operation. Serum and omental tissue were collected before, 24, and 48 h after CLP. Serum levels of adiponectin, cytokine, and chemokine were measured with ELISA. mRNA expressions in omental tissues were determined by RT-PCR. Survival was monitored for 7 d after CLP.
Survival after CLP was significantly better in the pioglitazone/CLP than in the vehicle/CLP. Serum adiponectin levels before CLP were higher in the pioglitazone/CLP than in the vehicle/CLP. Treatment with pioglitazone significantly inhibited the increases in the serum interleukin-6 and monocyte chemoattractant protein-1 (MCP-1) levels after CLP and lowered the mRNA expressions of proinflammatory cytokines, interleukin-6, and MCP-1 in omental tissue after CLP.
The anti-inflammatory effects of pioglitazone on omental adipocyte function appear to be mediated in part by PPAR-γ activation, which down-regulates the production of inflammatory mediators.
The pathogenesis of ischemia-reperfusion (I/R) injury is known to involve cytokines and, in particular, surface adhesion molecules, the expression of which initiates inflammatory cell attachment. It has been suggested that peroxisome proliferator-activated receptor (PPAR)-γ is an important immunomodulatory factor as well as a regulator of fatty acid. In this study, we investigated the expression of PPAR-γ in a renal I/R injury rat model. The right kidney was harvested and the left renal artery and vein were clamped by means of a laparotomy. The kidney was reperfused following 90 min of ischemia. Rats were sacrificed at 0, 1.5, 3, 5, 12 and 24 h after reperfusion. PPAR-γ expression was analyzed by immunohistochemical staining using monoclonal antibody. PPAR-γ staining was weak in the endothelial cells, interstitial cells and collecting ducts in the normal kidney. From 1.5 to 5 h after reperfusion, PPAR-γ staining was strong. Twelve hours after reperfusion, necrosis had extended throughout the kidney, and nearly all the tubular epithelial cells were destroyed. However, 12 h after reperfusion, PPAR-γ staining was weak in the endothelial cells and its expression was moderate in the interstitial cells and collecting ducts. PPAR-γ was induced in the endothelial cells, including the mesangial cells, interstitial cells and collecting ducts in a rat model of renal I/R injury.