| BackgroundTrauma is a leading cause in young patients and still a major public health problem around the world. At present, although severe trauma patients could survive in traumatic injury with great development in treatment and care system,the complications of trauma patients are still the main reason of in-hospital death. Therefore, predicting and preventing the occurrence of traumatic complications in first time may be an effective way to treat trauma patients. As we all known,sepsis and multiple organ dysfunction syndrome (MODS) are known as common and severe complications in trauma patients. Inappropriate inflammatory response of host organism to the invasion of microorganisms plays a fundamental role in the development of sepsis and the generation of inflammatory factors could contribute to vascular coagulation and MODS. This mechanism may help identify high risk factors of sepsis and MODS.IL-6 is a proinflammatory cytokine secreted by monocytes, endothelial cells and fibroblasts,and is able to stimulate B and T lymphocytes and induce fever. Some studies have suggested that IL-6 may play a key role in the inflammatory response to microbial invasion.TLR2, a key member of TLRs family,could recognize a variety of bacterial lipoproteins.Several studies have considered TLR2 as the initial barrier against infection. More and more studies have tried to explore the associations between single nucleotide polymorphisms (SNPs)in these two genes and the risk of sepsis. Among them, the roles of IL-6-174G/C polymorphism and TLR2 Arg753Gln polymorphism in the development of sepsis were widely discussed. However, the results were inconsistent. Therefore, we performed meta-analyses to further investigate the effect of IL-6-174G/C polymorphism and TLR2 Arg753Gln polymorphism on sepsis risk.Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors,which play important roles in metabolism, cellular proliferation, differentiation, and immune response. At present, there are three primary isoforms identified in PPAR family: PPARa,PPARβ/δ and PPARy. In addition to the well-studied roles of PPARs on metabolism, more and more studies have tried to explore the roles of PPARs in the development of inflammatory diseases, such as inflammatory bowel disease, tumour and proteinuric kidney disease. The mechanism of PPARs anti-inflammatory properties may be associated with the transrepression of NF-κB target genes. In addition, PPAR ligands could inhibit the recuitment of leukocytes to the site of inflammation. Therefore, it would be interesting to survey the potential roles of PPARs in the development of sepsis and MODS. Recently, accumulating studies have indicated that single nucleotide polymorphisms (SNPs) are important factors, which could affect inflammatory responses in traumatic patients. Although some researchers have investigated the effect of single nuclear polymorphisms in PPAR family genes on some inflammatory diseases, little was known about the roles of allelic variation in PPAR family genes in the development of sepsis and MODS in traumatic patients. Under these circumstances, we explored the association between SNPs identifying within PPAR family genes and the risk of sepsis and MODS in traumatic patients.Methods1. meta-analysisWe searched all published papers in PubMed, Embase and Web of Knowledge databases.Relevant studies were retrieved and their references were checked to obtain other relevant publications. Corresponding inclusion criteria and exclusion criteria were used to evaluate the retrieved papers. Two investigators independently conducted the process of data extraction.Because the model of inheritance of sepsis is unknown, we performed the meta-analysis with the allele comparison model (A vs. B), the codominant model (AA vs. BB), the recessive model (AA vs. AB/BB) and the dominant model (AA/AB vs. BB). Odds ratios and corresponding 95% confidence intervals were used to assess the association between corresponding SNPs and sepsis risk. Z test was selected to evaluate statistical significance of pooled ORs. In addition to total analyses,we also performed subgroup analyses. Further,heterogeneity analysis, sensitivity analysis and publication bias were also conducted,respectively, to evaluate the association between corresponding SNPs and sepsis risk.2. Identification of haplotype tag single nucleotide polymorphisms within thePPAR family genes and their clinical relevance in patients with major traumaSeven hundred and thirty-four unrelated Chinese Han trauma patients living in Chongqing district were included in our study. Our observed sequence of human PPAR family genes contained all regions from 3 kb upstream of the transcription start site to 3 kb downstream of the stop codon. All of the SNPs within the study regions were identified from the HapMap database (www.hapmap.org). Haploview (version 4.2) was used to construct haplotype blocks throughout the entire PPARα, β/δ and γ genes, respectively. Tag SNPs were selected from the observed regions within PPAR family genes. Improved multiplex ligation detection reaction (iMLDR) technique was used for genotyping according to a previous report.In addition, tumor necrosis factor a (TNFa) production of peripheral blood leukocytes was also analyzed by enzyme linked immunosorbent assay after lipopolysaccharide (LPS)stimulation.Results1. Meta-analysisTwenty studies on the risk of sepsis and seven studies on sepsis mortality were included to evaluate the association between IL-6-174G/C polymorphism and sepsis risk. None of the results showed evidence of a significant association between IL-6-174G/C polymorphism and sepsis risk in overall analysis or subgroup analyses based on sepsis type, ethnicity, source of control and age under any genetic model (the allele comparison, the codominant, the recessive or the dominant model). Although there was a statistically significant association between IL-6-174G/C polymorphism and sepsis-related mortality under the recessive model, the significance did not exist after Bonferroni’s correction.Twelve studies with 898 cases and 1517 controls were included to evaluate the association between TLR2 Arg753Gln polymorphism and sepsis risk. There were significant associations between TLR2 Arg753Gln polymorphism and sepsis risk in overall analyses under two genetic models (the allele comparison and the dominant model). In addition,subgroup analyses based on age group, ethnicity, sepsis type and source of control also showed the significant effect of TLR2 Arg753Gln polymorphism on sepsis risk.2. Identification of haplotype tag single nucleotide polymorphisms within the PPAR family genes and their clinical relevance in patients with major trauma All patients survived at least 48 h after admission. Among them, three hundred patients have developed sepsis in our population cohort, and pathogens were found in the blood cultures of 138 septic patients (46.0%). Organ dysfunction was found in 374 (51.0%)individuals in our study among whom, 116 (31.0%) had two or more organ dysfunctions.Respiratory tract infection was the main type of infection in our study cohort. There were total nine tag SNPs (rs135551,rs5769178,rs4253711, rs4823613,rs6902123,rs2016520,rs4684846, rs10865710 and rs1822825) included in our study. All tag SNPs were located in intron excepted for rs2016520 (5’UTR) and rs10865710 (Exon A2). In our cohort,the minor allele frequencies of nine tag SNPs were 7.6% (rs135551), 15% (rs5769178), 14.4%(rs4253711), 23.2% (rs4823613), 3.1% (rs6902123), 30.4% (rs2016520), 45.8% (rs4684846),34.6% (rs10865710) and 45.5% (rsl822825), respectively. In addition, the genotype distribution of all the nine selected SNPs was consistent with HWE. There were no significant differences in age, gender ratio or ISS among patients with different genotypes of each selected SNP. The patients carrying G allele of the rs10865710 polymorphism significantly increased the risk of sepsis and MODS when compared to those carrying C allele (P=0.002 for development of sepsis and P=0.041 for MOD scores in case of recessive effect, P=0.046 for development of sepsis in case of dominant effect). After regression analysis,there was also a significant association between this polymorphism and sepsis risk under the allele comparison model (OR=1.461, 95% CI: 1.159-1.843, P=0.001). However, other selected SNPs were not significantly associated with the risk of sepsis or MODS in our present study.There were sixty whole-blood samples from trauma patients included to evaluate the level of TNFa (n=20 for the CC genotype, n=20 for the GC genotype and n=20 for the GG genotype).Results showed that the rs10865710 polymorphism was associated with the TNFa production of LPS-induced peripheral blood leukocytes. The level of TNFα production was higher in patients with G allele compared to those with C allele (P=0.027 for recessive effect and P=0.041 for dominant effect).ConclusionsOur present study supported a direct effect of TLR2 Arg753Gln polymorphism on sepsis risk, especially in European. TLR2 Arg753Gln polymorphism might be used to estimate the risk of sepsis. However, current evidence did not support a direct effect of IL-6-174 G/C polymorphism on the risk of sepsis. In addition, there was no association between IL-6-174 G/C polymorphism and sepsis mortality after Bonferroni’s correction. Further analyses of gene-environment interactions and more studies based on larger sample size and homogeneous sepsis patients are required.In addition,there were nine tag SNPs identified within the study regions of PPAR family gens. We found that the rs10865710 polymorphism in PPARy gene was associated with the development of sepsis and MODS in Chinese Han trauma patients. Further study suggested that this polymorphism could affect the TNFa production of LPS-induced peripheral blood leukocytes. Therefore, it might be used to estimate the risk of sepsis and MODS among trauma patients. In the future, large well-designed studies are needed to confirm the significance of these findings. |
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