The immune efficacy outcomes of ω-3 polyunsaturated fatty acid-supplemented parenteral nutrition in patients with gastrointestinal malignancy were compared.+, CD4+, CD4+/CD8+ in the omega-3 group were significantly higher than those in the control group . In the humoral immunity: The levels of IgA, IgM and IgG in the omega-3 group were significantly higher than those in the control group . The count of lymphocyte in the omega-3 group was significantly higher than that in the control group . In the postoperative inflammatory cytokine: The levels of interleukin-6, tumor necrosis factor (TNF)-α and C-reactive protein in the omega-3 group were significantly lower than those in the control group . The rate of postoperative infective complications in the omega-3 group was significantly lower than that in the control group .Sixteen RCTs involving 1008 patients  were enrolled into the analysis. The results of meta-analysis: the cell immunity: The proportions of CD3This meta-kanalysis confirmed that early intervention with Omega -3 fatty acid emulsion in gastrointestinal cancer can not only improve the postoperative indicators of immune function, reduce inflammatory reaction, and improve the postoperative curative effect but also improve the immune suppression induced by conventional PN or tumor. Therefore, postoperative patients with gastrointestinal cancer should add omega-3 unsaturated fatty acids in their PN formula. Further high-quality RCTs are needed to verify its efficacy. Essential fatty acids for the human body are the omega-6 group linoleic acid and omega-3 group alpha linolenic acid, which are both polyunsaturated fatty acids (PUFA). PUFA can be divided into 4 families—omega-3, omega-6, omega-7, and omega-9. Among them, the omega-3 family mainly includes alpha linolenic acid, 20 carbon five acid (EPA), and 22 carbon six acid (DHA). Omega-3 fish oil fatty milk is extracted from deep sea fish oil, the main components of which are EPA and DHA. In recent years, studies have shown that omega-3 PUFA can increase the stability of the omega cell membrane, regulate immune function, block excessive inflammatory reaction,2, LTB4, and TXA2 by a series of enzymatic reactions. These substances are important proinflammatory mediators in inflammatory response and inhibit immune function. Omega-3 fish oil fat emulsion is effective in improving cellular immune function and inhibiting inflammatory response. The possible mechanism is that the EPA and DHA in omega-3 fish oil fat emulsion are further metabolized to PGE3, PGI3, TXA2, and LTB5, which can competitively inhibit the release and metabolism of arachidonic acids (AA), thereby reducing the body's inflammatory response and protecting from immune-mediated damage. In addition, EPA and DHA can also change the lipid composition and cell function of T-lymphocyte membrane, increase cell membrane stability, and affect the cellular immune function.,3Traditional fat emulsion, such as long chain fatty emulsion (LCT), is primarily sourced from soybean oil, and its main component is omega-6 fatty acid. Arachidonic acid, an important derivative of linoleic acid, synthesizes PGI However, the results and conclusions of these studies were not entirely consistent owing to limited sample size, different study designs, and potential bias. Therefore, we performed a meta-analysis of all relevant randomized control trials (RCTs) with the main focus on the efficacy of omega-3 PUFAs on inflammatory and immune function in postoperative patients with gastrointestinal malignancy.Some studies have investigated the efficacy of omega-3 PUFA-enriched nutrition for patients with gastrointestinal malignancy undergoing surgery, and the primary results indicated that the immunological function of omega-3 PUFAs would be helpful in preventing postoperative infectious complications.22.1We searched for journal articles published from January 2000 to June 2017 both electronically and manually. We searched the databases of PubMed, the Cochrane Library, Web of Science, EMBASE, and the Chinese Biomedicine Database for the following search terms: (“omega-3” OR “n-3” OR “polyunsaturated” OR “FO” OR “omega-3 fatty acid” OR “n-3 polyunsaturated fatty acid”) AND (“fatty acid” OR “fish oil”) AND (“cancer” OR “carcinoma” OR “tumor” OR “neoplasms”) AND (“surgery” OR “operation”) AND . Both MeSH words and free terms were included in the search. No language restriction was applied and the search was performed by 2 independent researchers. Final inclusion of articles was determined by consensus; when this failed, a third author adjudicated. The results of the search strategy are shown in Fig. 2.2Studies that met the following criteria were included: studies that evaluated the inflammatory and immune function of omega-3 PUFA-enriched nutrition for patients undergoing surgery for gastrointestinal malignancy. The omega-3 PUFAs should have been administered as an adjuvant in the study group (omega-3 group), and the duration of administration had to be short-term postsurgery; the study was the most recent publication in the case of multiple publications; and RCTs that had access to the full-text.2.3The following studies were excluded: those wherein details of PN were not available; those with no comparison of omega-3 group and control group; those in which the study outcomes did not include complete or available postoperative data; those which reported data used in a later study; and case reports, abstracts, letters, comments, and reviews without original data, and studies that presented insufficient data.2.4+, CD4+, CD8+ cell counts and CD4+:CD8+ ratio; lymphocyte count; and the incidence of postoperative infectious complications.The following detailed data were independently extracted by 2 investigators and checked by the other authors: title; authors; year of publication; country; study design; number of patients; interventions ; postoperative serum inflammatory cytokines ; postoperative humoral immune function markers such as immunoglobulin  levels; cellular immune function CD32.5I2 tests were used to test the heterogeneity between studies. I2 > 50%, this suggested significant heterogeneity, a random effects model was applied. If I2 < 50%, this suggested not significant heterogeneity, a fixed effects model was applied. If P < .05, this considered statistically significant. Funnel plots were used to evaluate potential publication bias.Meta-analysis was conducted with Review Manager (version 5.3.0) software. Odds ratios (ORs) used to analysis the categorical variables and 95% confidence interval (CI) values were reported. Weighted mean difference (WMD) used to analysis the continuous variables and 95% CI values were reported. The Mantel–Haenszel, Chi-square, and 2.6In this meta-analysis, 16 randomized clinical trials RCTs were included. The total number of patients was 1008, of whom 506 was omega-3 group and 502 was control group. The characteristics of all the included studies are shown in Table 2.7For the included RCTs, assessment of the bias risk involved 6 parameters: sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting bias, and other potential sources of bias Fig. .33.1The statistical findings of meta-analyses comparing postoperative outcomes of ω-3 group and control group are summarized in Table 3.23.2.1+ cell counts (%). The results of meta-analysis show that the value of postoperative CD3+ cell counts increased in response to ω-3 PUFA supplementation . Therefore, using a fixed model , we pooled data from the 12 studies to comparing ω-3 group with control group. The results of meta-analysis show that the value of postoperative CD4+ cell counts increased in response to ω-3 PUFA supplementation . Therefore, using a fixed model , we pooled data from the 11 studies to comparing omega-3 group with control group. The results of meta-analysis indicate that there is no significant difference between the 2 groups in terms of postoperative CD8+ cell counts . Therefore, using a fixed model . Therefore, using a random model . Therefore, using a fixed model . We pooled data from the 6 studies to comparing ω-3 group with control group. The results of meta-analysis show that the value of postoperative immunoglobulins A increased in response to ω-3 PUFA supplementation . Therefore, using a fixed model . The results of meta-analysis show that the value of postoperative immunoglobulins M increased in response to ω-3 PUFA supplementation . Therefore, using a fixed model . The results of meta-analysis show that the value of postoperative immunoglobulins G increased in response to ω-3 PUFA supplementation . The results of meta-analysis show that the value of postoperative lymphocyte count increased in response to ω-3 PUFA supplementation . Therefore, using a fixed model . Therefore, using a fixed model . The results of meta-analysis show that postoperative values of IL-6 decreased in response to ω-3 PUFA supplementation . Therefore, using a fixed model . The results of meta-analysis show that postoperative values of TNF-α decreased in response to ω-3 PUFA supplementation . Therefore, using a fixed model . The results of meta-analysis show that postoperative values of CRP decreased in response to ω-3 PUFA supplementation . Therefore, using a fixed model , activate other cells so that they secrete lymphatic factors, and play a mediating role in inflammatory reactions. CD8+ T cells are a type of immune suppression cell, as they inhibit antibody secretion and T-cell proliferation, CD8+ cells may also represent cytotoxic cells. Some studies have shown that the ratio of CD3+, CD4+, and CD4+/CD8+ decreased and the ratio of CD8+ increased in the peripheral blood of patients in the first postoperative week, which was suggestive of inhibited cellular immune function. The ratio change due to surgical trauma and the body in high metabolic stress postsurgery resulted in inhibited T lymphocyte function, thereby reducing the number of cells and strength of the immune response. The results of our meta-analysis showed that the value of CD3+, CD4+, and CD4+/CD8+ ratio increased in ω-3 groups on the sixth postoperative day. The ratio of CD3+, CD4+ T lymphocyte subsets in ω-3 group was significantly higher than the control group, suggesting that the ω-3 unsaturated fatty acid can enhance postoperative cellular immunity of patients with gastrointestinal malignancy. Meanwhile, an increased ratio of CD4+/CD8+ can enhance cellular immunity, promote cell activation and differentiation, and enhance humoral immunity. This meta-analysis suggests that these indicators of cellular immune function of patients in the ω-3 group was better than that of the control group. Immunoglobulins are a group of proteins that act as antibodies and are mainly present in human blood, tissue fluids, and exocrine fluids. Immunoglobulins are an important index to examine the humoral immune function of an organism. This meta-analysis showed that there was a clear difference between the ω-3 and control groups in terms of IgA, IgG, and IgM levels on the sixth postoperative day. The results indicated that ω-3 PUFAs can improve indicators of cellular and humoral immune function.T lymphocyte-mediated cell-mediated immunity plays an important role in anti-tumor immune response.,33 TNF-α and IL-6 are pre-inflammatory factors that have an important role in induction and regulation of inflammatory response. TNF-α is a protein produced by LPS-stimulated monocyte macrophage, which is a promoter of multidirectional inflammation and inflammation. TNF-α can activate neutrophils, macrophages, and other inflammatory cells, and can induce IL-6 secretion by vascular endothelial cells. IL-6 is an important index to reflect the severity of inflammation and tissue damage. The results of our meta-analysis showed that there was a significant difference between the ω-3 groups and control groups with regard to TNF-α and IL-6 levels on the sixth postoperative day. The values of IL-6 and TNF-α were significantly lower in the ω-3 PUFAs group than the control group, thereby confirming that ω-3 PUFAs can significantly reduce the release of IL-6 and TNF-α in serum and reduce damage to the immune system and enhance immune function. CRP is an acute phase protein synthesized by IL-6-induction of hepatocytes. CRP levels show a rapid and sensitive change in acute trauma and infection and can reflect the change of inflammatory reaction in an organism. Continuous monitoring of CRP after operation is a sensitive index to determine the degree of postoperative stress response and infectious complications and is thus clinically significant. Studies have shown that the majority of patients showed an increase in CRP levels 4 to 12 hours after operation, which reached a peak at 24 to 72 hours, and returned to baseline 14 days after surgery. The results of our meta-analysis showed that the levels of CRP were significantly different between the 2 groups on the sixth postoperative day, with the control group showing significantly higher levels than the ω-3 group. This indicated that ω-3 PUFAs can reduce the postsurgical inflammatory reaction in patients with gastrointestinal tumors.TNF-α, IL-6, and CRP play an important role in response to tissue injury and inflammation in early trauma.Peripheral blood neutrophils, eosinophils, basophils, lymphocytes, and monocytes are important components of the body's defense system. In this study, lymphocyte count was significantly higher in ω-3 groups than the control groups. Omega-3 PUFAs improve the body's defense system by the proliferation of lymphocytes, and the meta-analysis result also confirmed that the incidence of infectious complications in ω-3 groups was significantly lower than the control group. Omega-3 PUFAs can regulate the release of inflammatory mediators and promote lymphocyte proliferation to improve the body's defense system, and improve postoperative outcomes in patients. Furthermore, Wei et al reported that ω-3 PUFAs can reduce the expression and level of tumor-related factors such as vascular endothelial growth factor and insulin-like growth factor-1, suggesting that ω-3 PUFAs had inhibitory effects on tumor growth. As all studies did not report the long-term survival of patients, it is necessary to further investigate the long-term clinical prognosis of patients with gastrointestinal cancer after the use of ω-3 PUFAs.A major limitation of our meta-analysis is that all the included RCTs were Chinese studies. Therefore, the conclusion may not be generalizable to other ethnic populations. Another potential limitation is that experience and methods of perioperative management used at different hospitals and specialist centers could have produced different outcomes and increased the heterogeneity among the included studies.5Omega-3 fatty acids play an important role in the regulation of inflammatory factors and immune function and improve the nutritional status through a variety of mechanisms. The result of this meta-analysis confirmed that early intervention with ω-3 fatty acid emulsion in gastrointestinal cancer cannot only improve the postoperative indicators of immune function, reduce inflammatory reaction, and improve the postoperative curative effect but also improve the immune suppression induced by conventional PN or tumor. Therefore, postoperative patients with gastrointestinal cancer should add ω-3 unsaturated fatty acids in their PN formula. Further high-quality RCTs are needed to verify its efficacy.Writing – original draft: Yajie Zhao.Writing – review and editing: Chengfeng Wang.


IL-10) gene rs1800896 polymorphism with the risk of prostate cancer (PCa); however, their conclusions were inconsistent. Therefore, we conducted this meta-analysis to evaluate the role of IL-10 rs1800896 polymorphism in the risk of PCa. 16 eligible studies in 15 articles involving 6,301 cases and 6,510 controls were identified by researching PubMed, Google, CNKI, and EMBASE up to April 1, 2017. Our results revealed that IL-10 rs1800896 polymorphism was associated with the decreased risk of PCa under the homozygous model. Subgroup analysis by ethnicity revealed that rs1800896 polymorphism decreased the risk of PCa among Caucasians. In conclusion, IL-10 gene rs1800896 polymorphism is associated with the decreased risk of PCa. Larger studies with more diverse ethnic populations are needed to confirm these results.Numerous studies have uncovered the association of Interleukin-10 ( IL-10) could significantly predict the risk of PCa [Prostate cancer (PCa) is the most common malignancy diagnosed in men and the second leading cause of cancer-related death for men in the United States . The Amek of PCa .IL-10 is a pleiotropic cytokine that modulates the function of several adaptive immunity-related cells [IL-10 is known to suppress the functions of both T lymphocytes and macrophages, working as a general dampener of the immune and inflammatory responses [IL-10 could suppress metastasis and growth of the tumor by inhibiting macrophage-derived angiogenic factors in vivo [IL-10 transfected into Chinese hamster ovary cells prevents tumor growth and macrophage infiltration [IL-10 was observed in PCa tissue by the analysis of type T1 and T2 cytokines in patients with PCa [IL-10 decreased stemness of human prostate cancer cells in vitro [IL-10 may provide insights about screening and therapeutic intervention on neoplastic patients.ed cells . IL-10 iesponses . Huang e in vivo . Richterltration . In addiin vitro . Based oIL-10 rs1800896 polymorphism may have an influence on IL-10 mRNA expression and the expression of IL-10 in vitro [IL-10 rs1800896 polymorphism had effects on the risk of PCa. Some studies yielded relations between IL-10 rs1800896 polymorphism and PCa risk [IL-10 gene on PCa susceptibility in the overall population.Kingo et al. identified that in vitro . Recentlin vitro , 13–26 aPCa risk , 19, 22,PCa risk , 23-26. IL-10 and IL10 to identify relevant articles. Totally 195 articles were identified after an electronic and manual search . Then 67 duplicates and 96 articles unrelated to this topic were removed. 32 articles remained for further full-text review. 17 articles were excluded due to the following reasons: eight articles investigated other diseases rather than PCa; three articles investigated other polymorphisms of IL-10 gene; one article did not provide detailed genotyping data; three articles were reviews or meta-analyses; one article was excluded due to overlapping information with another study. One article was divided into two studies because it contains two different racial groups. Finally, 16 eligible studies in 15 articles with 6,301 patients and 6,510 controls were included in this meta-analysis. The selection for eligible studies was presented in Figure We used the following searched terms like prostate cancer, prostatic neoplasm, prostate carcinoma, prostate neoplasms, polymorphism, polymorphisms, SNP, SNPs, rs1800896, Interleukin 10, IL-10 rs1800896 polymorphism and PCa was summarized in Tables P = 0.044, Figure IL-10 gene was associated with the decreased risk of PCa among Caucasians in most of the comparisons , HWE (P = 0.621) and genotyping method (P = 0.514) had no significant impact on the heterogeneity in ORs with IL-10 rs180086 polymorphism except for SOC (P = 0.043). Consequently, SOC may be the main source of high heterogeneity. We assessed the sensitivity by omitting each study in turn to assess the effect of individual study on the overall estimated risk. The pooled ORs did not show a significant difference by removing any individual study, supporting that this meta-analysis was stable and trustworthy  antigens on monocytes [IL-10 gene could reduce the production of IL-10 [IL-10 was beneficial for immunological monitoring, reducing the possibility of tumor cell survival. It may partly explain the reason why IL-10 gene rs1800896 polymorphism was associated with the decreased risk of PCa.Recently, a study found onocytes . The finof IL-10 . Based oThe stratified analyses further confirmed this significant association in population-based studies and studies using the genotyping method of MassARRAY. In addition, stratification analysis by ethnicity indicated that the G allele of rs1800896 could decrease the risk of PCa among Caucasians  and increase the risk of PCa among Asians (2 studies containing 360 cases and 358 controls), indicating different racial inheritance of Caucasians and Asians. This discrepancy may partly attribute to ethnicity-specific effect and sample sizes. For Caucasians, the minor allele G frequency was 0.467 in this meta-analysis, which was much higher than that of Asians (0.164). We hypothesized that genetic heterogeneity, clinical heterogeneity, different genotyping methods and random errors may also be the potential reasons for different findings between Asians and Caucasians. In addition, sample sizes in the subgroup of Asians were relatively small, thus the findings of Asians may be underpowered. Consequently, the results of Asian groups need be interpreted with caution. Further studies with larger sample sizes is necessary to confirm these hypotheses.IL-10 rs1800896 polymorphism and cancer risk [IL-10 rs1800896 polymorphism had no association with breast cancer risk in the overall population [IL-10 rs1800896 polymorphism and the decreased risk of PCa. In summary, the above findings may suggest that IL-10 rs1800896 polymorphism has disease-dependent functionality, which may explain the inherent heterogeneity of tumor progression in different types of cancer.Multiple meta-analyses were conducted to investigate the association between cer risk -42. The pulation . Howeverpulation , 42. In Several potential limitations should be addressed in this meta-analysis. First, no further stratification analyses of other potential factors, such as age and familiar history due to lack of original data. Second, our results were based on unadjusted estimates for confounding factors, which might have affected the final conclusions. Third, the sample sizes of some individual studies were very small, which could deviate from the true results. Fourth, the results should be interpreted with caution due to high heterogeneity. Fifth, some bias may be unavoidable because only articles published in English and Chinese were identified in this study. Finally, the sample sizes of Asian groups were limited.IL-10 gene rs1800896 polymorphism is associated with the decreased risk of PCa. IL-10 gene may have an ethnicity-specific effect and disease-dependent functionality. Larger studies with more diverse ethnic populations are needed to confirm these results of this meta-analysis.In conclusion, this meta-analysis indicates that IL-10” OR “IL10” OR “Cytokine Synthesis Inhibitory Factor”). References in cited studies and review articles were also checked for other relevant articles. We included the latest study when one study overlapped with another one. PCa was diagnosed according to classification criteria.PubMed, EMBASE, Google and CNKI databases were searched for all relevant articles up to April 1, 2017. The following search terms were used: (“prostate cancer” OR “prostatic neoplasm” OR “prostate carcinoma” OR “prostate neoplasms”) AND (“polymorphism” OR “polymorphisms” OR “variant” OR “SNP” OR “SNPs” OR “rs1800896”) AND  provided sufficient data for calculating the pooled odds ratio (ORs) with 95% confidence interval (CI); (3) were case-control studies. Exclusion criteria were: (1) studies containing overlapping data; (2) case reports or reviews; (3) articles investigating other SNPs of IL-10 gene.Studies were included if they: (1) discussed the association between the Two investigators extracted data from the original studies independently. From each study, the following information was extracted: name of the first author, publication year, country of origin, ethnicity, genotypes of cases and controls, and genotyping method. Authors were contacted to provide supplemental data if data were not available in the relevant articles.The Newcastle-Ottawa Scales (NOS) were used to assess the quality of the selected studies . Total NIL-10 rs1800896 polymorphism and the risk of PCa. Stratification analyses were carried out by ethnicity, SOC, HWE and genotyping method. Heterogeneity between studies was detected by Cochran’s Q-statistics. Generally, we considered the presence of significant heterogeneity at the 10% level of significance and values of I2 exceeding 50% as an indicator of significant heterogeneity. When no heterogeneity was found with P > 0.10 or I2 < 50%, a fixed-effect model was used. Otherwise, a random-effects model was applied [P < 0.05 was regarded as representative of statistical significance. All statistical analyses were performed using the Stata 11.0 software .Pearson’s χ2 test was used to evaluate whether gene frequencies in the controls conformed to HWE. Pooled ORs with corresponding 95% CIs were calculated to evaluate the strength of the relationship between  applied . To dete applied ; P < 0.0


Microtubule-associated protein tau (MAPT) gene is compelling among the susceptibility genes of neurodegenerative diseases which include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Our meta-analysis aimed to find the association between MAPT and the risk of these diseases. Published literatures were retrieved from MEDLINE and other databases, and 82 case-control studies were recruited. Six haplotype tagging single-nucleotide polymorphisms  and haplotypes (H2 and H1c) were significantly associated with the above diseases. The odds ratios (ORs) and 95 % confidence intervals (CIs) were evaluated by comparison in minor and major allele frequency using the R software. This study demonstrated that different variants in MAPT were associated with AD , PD , PSP , CBD  and ALS  instead of FTD . In conclusion, MAPT is associated with risk of neurodegenerative diseases, suggesting crucial roles of tau in neurodegenerative processes. MAPT) gene is compelling [MAPT have been reported to participate in AD [Neurodegenerative diseases are a group of disorders with progressive neuronal loss in particular regions of brain, including Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and many others. The etiology of neurodegenerative diseases is complicated and multifactorial, mainly including genetic variants and environmental exposure. However, epidemiologic evidence for the association between the environmental exposure and neurodegenerative diseases is not conclusive . Geneticmpelling . Mutatiote in AD –6, PD [7te in AD , PSP [10te in AD , CBD [12te in AD , FTD [14te in AD  and ALS te in AD , 17.MAPT is located on chromosome 17q21.3, and encodes six tau isoforms ranging from 352 to 441 amino acids in length expressed in neurons [MAPT have been proved pathogenic to neurodegenerative diseases [MAPT variants probably cause abnormal structure and function of hyperphosphorylated, insoluble and aggregated tau. These pathological changes are crucial for the pathogenesis of tau-related neurodegenerative diseases, which are called tauopathies [MAPT, H1 and H2. Several single-nucleotide polymorphisms (SNPs) throughout MAPT gene are in complete linkage disequilibrium (LD) and largely tags the H1 and H2 haplotypes, called haplotype tagging SNPs (htSNPs) [STH), nested in intron 9 of the MAPT, is in complete LD with the extended H1/H2 haplotype [MAPT variants with neurodegenerative diseases, while others showed none. The results of the related studies were inconsistent. neurons . To dateopathies . As know(htSNPs) . Six htS(htSNPs) , 21. The(htSNPs) . Additioaplotype , 24. Theaplotype , 24. UnfMAPT and their risk on neurodegenerative diseases.Therefore, we performed a meta-analysis by pooling the whole related data from previously studies to reach a more precise estimate of the relationship between variants in MAPT and neurodegenerative diseases were shown in Figure 5357 studies were retrieved through the literature search, and 1226 papers of these were identified as potentially meeting the inclusion criteria after reviewing the titles and abstracts. Besides, we included 148 studies by manual searching. After further reviewing the full text, 82 studies were identified eligible . The heterogeneity was reduced to 56.2% and the pooled effect was changed into negative  when one single study was excluded [Egger = 0.0499)  . Using tMAPT polymorphism in PD [A total of 32 studies were included in the meta-analysis of sm in PD , 60–85   and reduced to 42.5% when the three studies which did not report the HWE test was excluded. But the exclusion of the related study did not influence the statistical significances.Seven studies were included in the meta-analysis of m in FTD , 96, 97 m in FTD , 99. Thrm in FTD , 16, 20.) Figure . Mild heMAPT polymorphism in ALS [MAPT haplotypes and ALS. Notably, the H2 haplotype showed mildly protective effect on ALS risk  .Two studies were included in the meta-analysis of m in ALS , 17 (Supm in ALS . Like FT) Figure . No heteMAPT are associated with different neurodegenerative diseases. The minor alleles within rs1467967 and rs242557 are not all the same in different populations  tau [AD is histopathologically characterized by two neuropathological hallmarks: neuritic plaques primarily composed of extracellular Amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau protein . Obvious4R) tau , 48, 101R tau , 4(4R) tau . Notably(4R) tau . Hence, (4R) tau , 56. WheMAPT with PD [MAPT and PD. We found that rs242557, rs7521 and H2 haplotype were associated with PD in Caucasian. Besides, MAPT variants influence the susceptibility of PD risk mainly by affecting the levels of total or 4R tau [MAPT has been identified as a functional variant, which could affect the expression or splicing of MAPT, acting as cis-factors [MAPT haplotype with PD in non-Caucasians awaits further investigation.PD is the second most common neurodegenerative disease following AD. Recently, some genome-wide association studies (GWAS) have provided robust evidence for the genetic association of  with PD , 8, 73. r 4R tau . This prr 4R tau . Rs24255-factors , 104. Th-factors . This fi-factors . We confMAPT protein isoforms [PSP and CBD are two parkinsonian syndromes characterized by deposits of neurofibrillary tangles in the brain, which are mainly composed of 4R isoforms . In healisoforms . Probablisoforms , 95. Howisoforms , 95. HenMAPT gene had been detected in autosomal dominant FTD with parkinsonism (FTDP). In addition, the accumulation of aberrant tau protein was found in FTD. These findings suggested that MAPT may be a genetic risk factor for FTD. However, our meta-analysis was failed to find the MAPT haplotypes had been associated with FTD. We suggest that more studies on other variants in MAPT are needed to probe the association and also in other populations.FTD is a form of presenile dementia characterized clinically by behavioral and personality changes, mutism and decline of memory later in the disease , which nALS is a rarely progressive neurodegenerative disorder, but is the most common motor neuron disease in adult-onset. ALS is characterized by the simultaneous deficits of upper and lower motor neurons, which lead to muscle atrophy and paralysis . The hypMAPT are associated with neurodegenerative diseases risk. But there are several limits in our study. One limitation of our study is that the present studies were only limited to Caucasian populations in PSP, CBD, FTD and ALS, to our knowledge. What is more, in FTD and ALS, the studies were only limited to H1/H2 haplotype. Therefore, more studies are needed in the future, particularly those which performed in different populations and SNPs. Another limitation is different diagnostic criteria across studies. The accuracy of clinical diagnostic criteria is lower than pathological diagnostic criteria. For example, we assumed that about 6% of the patients had PSP but might be clinically diagnosed as PD by mistake [Our meta-analyses provide confirmatory evidence that multiple variants in  mistake . FurtherMAPT polymorphisms and neurodegenerative diseases so far. Our results robustly confirm the susceptibility role of MAPT in neurodegenerative diseases in a large meta-analysis, using highly informative htSNPs which capture 95% of MAPT haplotype diversity. Here we analyze these variants in MAPT and their association with neurodegenerative diseases as a step toward determining the precise mechanisms of genetic susceptibility for these group diseases. Significantly, this will have important implications for identifying potential therapeutic targets.In conclusion, this is the first comprehensive meta-analysis and systematic review which focused on the association between MAPT polymorphism with neurodegenerative diseases, we conducted a literature search in MEDLINE, EMBASE and the Cochrane library up to September 2016. We used the key search terms including “microtubule-associated protein tau”, “MAPT”, “saitohin”, “STH”, “polymorphism”, “Alzheimer's disease”, “Parkinson's disease”, “progressive supranuclear palsy”, “corticobasal degeneration”, “frontotemporal dementia”, “amyotrophic lateral sclerosis” and “neurodegenerative disease”, combined with Boolean operators as appropriate. Additional studies were obtained from the reference lists of relevant original studies or review articles.In order to identify the association between the MAPT polymorphisms and neurodegenerative diseases; (2) Case-control studies design; (3) Available allelic frequency for MAPT rs1467967, rs242557, rs3785883, rs2471738, rs7521, H2 and H1c haplotypes; Data of allelic frequency for estimating the OR with corresponding 95% CI were available in the report or could be calculated. We exclude the study, which the genotype frequency in the control group was not in HWE. Additionally, when two or more studies had overlapping participants, only the one with larger sample size was included.We assessed all studies if they meet the following criteria: (1) Evaluation of an association between Two reviewers independently read the studies and extracted data according to predefined criteria. Data of allelic frequency and its OR with corresponding 95% CI were extracted. Besides, the following information was extracted: author, publication year, state, ethnicity, diagnostic criteria, type of neurodegenerative diseases, sample size, mean age, the percentage of female, minor allele frequency, and the HWE test in each control group. The quality of studies was assessed with the Newcastle-Ottawa quality Scale (NOS): 1) the Selection; 2) the Comparability; 3) the Exposure . StudiesMAPT polymorphism and neurodegenerative disease, we calculated a pooled OR and 95 % CI using R software. The OR and 95 % CI were evaluated by comparison in minor and major allele frequency using the Pearson χ2 test or Fisher's exact test. We used the random-effects and fixed-effects model to calculate the subgroup and pooled ORs with 95% CIs in the presence and absence of heterogeneity, respectively. We assessed the heterogeneity by the Cochran Q and I2 . Publication bias was detected by Egger's test  [To determine the strength of associations between individual on bias) . When k on bias) . In addi


Matrix metalloproteinases (MMPs) polymorphisms have been implicated in the pathogenesis of glaucoma risk. However, the results were controversial. We performed a meta-analysis to evaluate the precise associations between MMPs polymorphisms and glaucoma risk.Related studies were reviewed by searching electronic databases within four databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between the most common polymorphisms of MMPs and glaucoma risk. Heterogeneity, publication bias and sensitivity analysis were conducted to guarantee the statistical power.P = 0.02, I2 = 0%), MMP-9 rs3918249 C > T polymorphism  and glaucoma risk in the general population. Subgroup analysis also suggested that MMP-9 rs17576 G > A was related to glaucoma in the Caucasian population .Overall, 11 selected articles involving 2,388 cases and 2,319 controls were included in this meta-analysis. Significant associations were only found between MMP-9 rs17576 G > A polymorphism (GA vs. GG: OR = 0.80, 95%CI = 0.67-0.97, Our meta-analysis demonstrates that MMP-9 rs17576 G > A polymorphism might be a protective factor against the development of glaucoma in Caucasian population. Glaucoma is a heterogeneous disease of the eye characterized by the progressive degeneration of retinal ganglion cells and loss of vision associated with elevated intraocular pressure (IOP) . After cAs we know, ocular hypertension is the most important risk factor for glaucoma, but its etiology is still unclear. Many molecular epidemiological studies have suggested that glaucoma is a complex multifactorial disease. Various risk factors such as diabetes, hypertension, lifestyle habits , age, and genetics play interacting roles in the development of glaucoma. Recently, certain genetic factors, including matrix metalloproteinases (MMPs), were found to be associated with glaucoma. MMPs are a group of zinc and calcium-dependent endopeptidases that are involved in extracellular matrix (ECM) homeostasis and remodeling , 5. In gPrevious molecular research has demonstrated that genetic mutations, including single nucleotide polymorphisms (SNPs), can alter the level of gene expression or the function of gene products, thereby affecting the susceptibility of individuals to specific diseases , 9. In 2This meta-analysis was conducted according to the guidelines of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) , 12. No Four online databases  were used to search for case control studies evaluating the association between MMPs polymorphisms and glaucoma risk published up to February 1, 2016, with the following search terms: “glaucoma,” “MMP,” “matrix metalloproteinases,” “polymorphism,” and “variant”. Manual searches of references from original studies and review articles on this topic were conducted to identify other relevant studies.The inclusion criteria for studies in our meta-analysis were as follows: (1) designed as a case control study, (2) reported an association between MMP polymorphism(s) and glaucoma risk,(3) sufficient genotype frequency to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and (4) no deviation from Hardy-Weinberg equilibrium (HWE) in the genotype distribution of the control group. For results that were reported in multiple publications, only the largest or latest dataset was included. The exclusion criteria included: (1) review articles, (2) case reports, (3) results without sufficient genotype frequency data, and (4) animal model research.Two reviewers (MYW and YW) independently reviewed the full articles and collected the following characteristics: the first author’s name, publication year, study country/region, ethnicity of participants (such as Asian or Caucasian), disease subtype, genotyping method, sources of controls, and frequencies of genotypes in glaucoma cases and controls. Hardy-Weinberg equilibrium (HWE) was estimated based on the genotypes of the controls. Discrepancies were resolved by discussion between the 2 reviewers or by consulting with an expert in ophthalmology (ZY).2 method [2 was less than 50% [P-values and P < 0.05 was considered statistically significant.Crude ORs with 95% CIs were calculated to evaluate the strength of the association between each reported MMP polymorphism and glaucoma risk. For the MMP-9 rs17576G > A polymorphism, the pooled ORs were obtained for the allele contrast (A vs. G), co-dominant , dominant (GA + AA vs. GG), and recessive (AA vs. GG + GA) models. Subgroup analyses according to disease type, ethnicity, study design, and genotyping methods were also conducted. Heterogeneity was assessed using Cochran’s Q statistic and the I2 method . ORs estthan 50% ; otherwithan 50% , 16. CumIn total, 45 related articles were identified. Seventeen of these studies were excluded through title and duplicate screening. Subsequently, 1 study was excluded for not involving glaucoma research; 2 studies without related polymorphisms locus were excluded; 6 studies were excluded for fundamental molecular biology researches; and 8 studies were excluded because they were reviews. Finally, 11 articles involving 2,388 cases and 2,319 controls met the inclusion criteria , 17–26 , MMP-9 rs3918249 C > T polymorphism  and glaucoma risk. Furthermore, in the subsequent analyses based on disease type, ethnicity, control design and genotyping methods, a significant protective effect against glaucoma risk was observed for MMP-9 rs17576 G > A in Caucasian populations   involving 2,028 cases and 1,794 controls were included in our analyses of the 6 most commonly reported SNP loci. Overall, significant associations were only found between MMP-9 rs17576 G > A polymorphism , indicating that there was no detectable publication bias.Sensitivity analyses were conducted by deleting each included study step by step in MMP-9 rs17576 G > A polymorphism. No single study qualitatively changed the pooled ORs when removed, indicating that the results of this meta-analysis are stable  involving 1,065 cases and 836 controls and 2 articles  with 792 cases and 559 controls were included in our meta-analysis of the MMP-1 rs1799750 1G > 2G and MMP-2 rs243865 C > T polymorphisms and glaucoma risk. No significant association was found for all models for these 2 SNP loci , can degrade and remodel ECM molecules, thereby influencing cellular activities and maintaining the homeostasis of theepithelialbasementmembrane , 28. TheP = 0.03). Subsequently, more epidemiological studies were conducted, with inconsistent and even contradictory results.SNPs are the most common type of genetic mutation and have been associated with altered disease susceptibility through changes in gene transcription and expression as well as amino acid substitutions. In 2006, Wang et al. conducted the first case control study investigating the potential association between MMP-9 SNPs and primary angle-closure glaucoma. Significant differences in the frequencies of the MMP-9 rs17576 G > A SNP genotypes were found between the glaucoma and healthy control groups, which suggested an increased risk for glaucoma in the Chinese population according to a dominant model  conferred different significantly susceptibility to glaucoma. Stratified analysis by ethnicity, control design, and genotyping method were performed to estimate the association for each subgroup. The subgroup analysis according to ethnicity demonstrated a significant protective association between the MMP-9 rs17576 G > A polymorphism and glaucoma susceptibility in the Caucasian population. Thus, ethnic differences may be the most important factor underlying differences in glaucoma susceptibility between the Asian and Caucasian populations. MMP-9 rs17576 polymorphism is locate in exon 6 of MMP-9 gene with a nucleic acid substitution from G to A, and this mutation located fibronectin type II domains that presumably enhance substrate binding , 35. AltTo the best of our knowledge, this is the first comprehensive meta-analysis evaluating the potential association between MMP gene polymorphisms and glaucoma susceptibility. Some limitations of this meta-analysis were inevitable and should be addressed. First, the number of included studies and the amount of data available were limited, which constrained the statistical power. Second, heterogeneity was observed in the data for some SNP loci, which further hindered our ability to confidently identify any potential associations. Third, due to the deficiency of available data, it was not possible to study the interactions between MMP gene SNPs and glaucoma risk factors, such as haplotype, tobacco smoking, alcohol drinking, hypertension, and diabetes mellitus.Despite these limitations, the findings further enhance our understanding of the potential associations between MMP gene polymorphisms and glaucoma susceptibility. Positive aspects of the analysis were also identified. First, the distributions of genotypes in the control subjects for all of the investigated SNPs conformed to HWE. Second, evaluation using Egger’s test and Begg’s funnel plots did not show significant publication bias. Third, a large amount of heterogeneity was alleviated through subgroup analyses.In conclusion, our meta-analysis indicated that the MMP-9 rs17576 G > A polymorphism maybe an important protective factor against glaucoma, especially in the Caucasian population. Moreover, the present findings highlight the need for further investigations of the potential associations between MMP gene polymorphisms and glaucoma, which should ideally large sample sizes and multiple ethnic groups.


AMPD1 gene C34T polymorphism on cardiac function indexes, blood pressure and prognosis in patients with cardiovascular diseases (CVD).The meta-analysis was aimed to evaluate the effects of Eligible studies were retrieved through a comprehensive search of electronic databases and manual search. Then the high-quality studies met the rigorous inclusion and exclusion criteria, as well as related to the subject was selected for the study. Comprehensive data analyses were conducted using STATA software 12.0.AMPD1 C34T polymorphism presented elevated left ventricular ejection fraction (LVEF) (%) and reduced left ventricular end diastolic dimension (LVEDD) (mm) as compared with CC genotype, moreover, the subgroup analysis found that the LVEF (%) was markedly higher in heart failure (HF) patients carrying CT + TT genotype than CC genotype. Besides, the systolic blood pressure (SBP) (mmHg) in CVD patients with CT + TT genotype was obviously decreased in contrast with the CC genotype. Patients suffered from HF with different genotypes (CT + TT and CC) of AMPD1 C34T polymorphism exhibited no significant differences in total survival rate and cardiac survival rate.The study results revealed that CVD patients with CT + TT genotype of AMPD1 gene C34T polymorphism may be correlated with LVEF, LVEDD and SBP, which plays a protective role in the cardiac functions and blood pressure in CVD patients, but had no effects on total survival rate and cardiac survival rate for HF.Our current meta-analysis indicated that the T allele of  Cardiovascular disease (CVD), a series of diseases involving the heart or blood vessels of people, has become one of the predominant causes of morbidity and mortality worldwide threatening human health according to W.H.O statistics –3. At prAMPD1 gene encodes the adenosine monophosphate deaminase (AMPD), a crucial enzyme in purine nucleotide and energy metabolism especially in skeletal muscle, as well as in cardiac muscle, with the function of catalyzing adenosine monophosphate to inosine monophosphate [AMPD1 gene is prevalently localized in chromosome 1 in the region p13 ~ 21 with 20 kb spanning in length, and consisting of 16 exons and 15 introns [AMPD1, contributing to the appearance of a premature stop codon, which leads to some related metabolic muscle diseases due to the AMPD activity deficiency [AMPD1 may play essential roles in the initiation and development of CVD, for instance, it has been demonstrated that AMPD1 allele mutation play a protective role during congestive heart failure (CHF) development, which contributed to prolong possibility of survival without cardiac transplantation [AMPD1 as a possible candidate gene is related to CVD. But the effect of AMPD1 C34T polymorphism in CVD remains controversial, like Collins RP and his team, who have yielded conflicting results stating that the mutant T allele of AMPD1was deleterious in both HF and post-MI patients who had myocardial infarction histories [AMPD1 genetic mutation on the prognosis and survival in CHF patients [AMPD1 gene C34T variant and CVD risk regarding the aspects of cardiac indexes, blood pressure and prognosis, and thereby deriving a more plausible estimation for CVD.The hosphate , 10. To  introns . Under mficiency . While sistories . BesidesAMPD1 gene C34T polymorphism and CVD were retrieved by using following ten English and Chinese databases  from inception through March 2017 with the following search terms: (“AMPD1” OR “Adenosine monophosphate deaminase 1”) and . In addition, we also carried out a manual search to find potential relevant studies.Published literatures about AMPD1 gene C34T polymorphism with blood pressure, cardiac function and prognosis in CVD patients; (2) studies in which could obtain the parameters  of CVD patients carrying CT + TT and CC genotypes of AMPD1 gene C34T polymorphism and calculate WMD (95%CI) and HR (95%CI); (3) unlimited sample size; (4) reliable detection of polymorphic loci; (5) with the same or overlapping data published by the same authors, the most recent or complete articles with the largest sample size; (6) only English or Chinese publications. Literatures that did not conform to the above inclusion criteria or involve one of the following criteria must be eliminated: (1) the literature with only overview and summary (without data) or meeting abstracts; (2) articles with insufficient data; (3) unpublished documents; (4) duplicated publications.The inclusion criteria were as follows: (1) associations of AMPD1 gene C34T polymorphism; (7) LVEF (%), LVEDD (mm), SBP (mmHg), diastolic blood pressure (DBP) (mmHg), total survival rate and the cardiovascular incidence in patients with different genotypes of AMPD1 gene C34T polymorphism.Two researchers independently searched and reviewed to extract available literature data based on the selection criteria. Disagreements were handled by discussions. The following major information was collected: (1) first author’s name; (2) publication year; (3) age, gender ethnicity and country of subjects; (4) type of diseases; (5) genotyping technology; (6) sample size of the CVD patients carried with different genotypes of http://sourceforge.net/) and the method [AMPD1 gene C34T polymorphism were evaluated using weighted mean difference (WMD) or hazard ratio (HR) and 95% confidence interval (95%CI), and Z test was used to compare the significance of the combined effects [Ph < 0.05 was considered significant) and I2 tests (I2 > 50%) were used to measure heterogeneity between the studies. The random-effects model was used for significant heterogeneity, while the fixed-effects model was conducted when no significant heterogeneity was existed [P < 0.05 was statistically significant difference.Meta-analysis was performed by STATA 12.0  software. Kaplan-Meier survival curves were used for HR and 95%CI calculation with the aid of software Engauge Digitizer Version 4.1  were retrieved in the initial literature search, of which 108 unrelated articles falling short of titles or abstracts were removed, and the remaining 94 articles were used for further screening. Then, 80 studies of these 94 papers were excluded after more detailed reviewing the full texts, 6 articles with insufficient data and 2 duplicates were removed. Finally, only 8 articles were considered eligible to be incorporated into the meta-analysis [A total of 206 studies related to analysis , 21–24. I2 = 0.00%, Ph = 0.566; LVEDD: I2 = 58.6%, Ph = 0.064). The meta-analysis showed that, as compared with CC genotype, LVEF (%) was significantly increased in CT + TT genotype , and accordingly, the fixed effect model was used. SBP (mmHg) was significantly lower in CVD patients with the CT + TT genotype compared with CC genotype by meta-analysis , thus the random effects model was selected. Two studies were about the effects of AMPD1 gene C34T polymorphism on cardiac survival rate, and it was proved to be with heterogeneity , and the fixed effect model was preferred. Among 4 studies, two suggested that AMPD1 gene C34T polymorphism of (CT + TT) enhanced the total survival rate of patients, while the other two found that it had no effects on the total survival rate and cardiac survival rate. Meta-analysis results showed that there were no distinctly differences in total survival rate and cardiac survival rate in CAD patients with different AMPD1 gene C34T polymorphism genotypes , blood pressure (SBP and DBP) and cardiac survival rate , LVEDD (mm), SBP (mmHg), DBP (mmHg), total and cardiac survival rate of CVD.The present meta-analysis has combined and reanalyzed 8 publications involving 2805 cases of patients with CVD, to assess the effect of AMPD1 gene C34T polymorphism was significantly increased in comparison to those patients with CC genotype. On the contrary, the CVD patients with CT + TT genotype had a greater reduction of LVEDD (mm) than those with CC genotype. In addition, our subgroup analysis according to the patients with or without HF verified that the LVEF was markedly higher in HF patients who carried with CT + TT genotype than CC genotype. As is known to all, abnormalities of left ventricle (LV) function or structure has been a common event among most CVD patients, demonstrating a negative influence on cardiovascular prognosis [AMPD1 C34T could weaken the AMPD activity, and promote the elevated circulating levels of adenosine, a crucial protective agent, which was in part the consequence of the attenuation of myocardial fibrosis and ventricular remodeling, and thus contributing to less severe CVD [AMPD1 was smaller, further indicating that the AMPD1 C34T polymorphism might affect different types of ventricular remodeling among CVD. Interestingly, no relevance of AMPD1 gene C34T polymorphism to LVEF (%) had been found in our 5 included researches [AMPD1 C34T polymorphism is remarkably correlated with lower levels of SBP, indicating that T allele carriers of this SNP may benefit for CVD individuals, as it have a decreased risk of developing the CVD pathologic state through a lower value of SBP. As shown by Safranow K, T allele carriers tended to have lower SBP than wild type in patients with CAD and HF, especially in ischemic HF patients, what might account for the lower fasting serum glucose or the higher creatinine clearance due to the T allele in patients with HF [AMPD1 variant performed a protective effect on cardiac function recovery.Our study showed that LVEF (%) in CVD patients with T allele of rognosis , 26. Whirognosis . As for rognosis . More imrognosis . Probablvere CVD , 30. Convere CVD  and Gastvere CVD  pointed searches , 21, 24, with HF . TherefoAMPD1 genetic mutation in HF patients, but failed to find any significant differences between different genotypes (CT + TT and CC) of this polymorphism and total survival rate and cardiac survival rate. It may therefore be possible that adenosine concentration in plasma (or muscle) of different genotypes showed no differences although T allele could induce the synthesis of myocardial adenosine [AMPD1 genotype had no statistically influences on the survival of HF [In addition, the present meta-analysis further explored the possibility of a relative survival and cardiovascular incidence benefit for the denosine , 33. Mordenosine , 35. Oural of HF . Similaral of HF .There are several limitations of the current meta-analysis need to be pointed out. First, as we know, heart failure can be caused by atherosclerotic and non-atherosclerotic factors, but we couldn’t conduct a subgroup analysis due to the fact that the included studies didn’t analyze the effects of AMPD1 gene C34T polymorphism on cardiac index, blood pressure and prognosis in patients with HF based on the etiology.. Second, heterogeneity in our study may influence the reliability of our results, although subgroup analysis was conducted to detect the heterogeneity source, as well as sensitivity analysis was introduced to appraise the stability of the results. Third, the data extracted from each record were based on unadjusted estimates, which may lead to misleading results. Fourth, we did not obtain all desired information from all materials because of the small number of studies. Fifth, the relatively small sample size of our study might have negative impact on the power of our meta-analysis. Lastly, the limited English and Chinese studies might also lead to language bias despite no evidence of publication bias from our statistical tests.AMPD1 gene C34T polymorphism was correlated with LVEF (%), LVEDD (mm) and SBP (mmHg) of CVD, which plays a protective role in the recovery of ventricular remodeling and cardiac function, as well as blood pressure, but has no influences on the total survival rate and cardiac survival rate of HF patients. Further well-designed researches with large sample size and complete clinical data are needed to test and verify our findings.In conclusion, our meta-analysis suggested that T allele of


Many molecular epidemiologic studies have explored the possible links between interleukin-12 (IL-12) polymorphisms and various cancers. However, results from these studies remain inconsistent. This meta-analysis is aimed to shed light on the associations between three common loci  of IL-12 gene and overall cancer risk. Our meta-analysis finally included 33 studies comprising 10,587 cancer cases and 12,040 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the cancer risk. We observed a significant association between IL-12B rs3212227 and overall cancer risk, especially in hepatocellular carcinoma, nasopharyngeal cancer, and among Asians. IL-12A polymorphisms (rs2243115 and rs568408) were found no influence on overall cancer risk. Nevertheless, stratification analyses demonstrated that rs568408 polymorphism contributed to increasing cancer risk of Caucasians and cervical cancer. And, rs2243115 may enhance the risk of brain tumor. These findings provided evidence that IL-12 polymorphisms may play a potential role in cancer risk. Cancer statistics, 2017, around 1,688,780 new cancer patients and 600,920 cancer-related deaths will develop in America in 2017 [According to the data provided by  in 2017 . In fact in 2017 . For ins in 2017 . LikewisIL-12 is mainly produced by activated antigen-presenting cells, such as macrophages, dendritic cells, and monocytes. As a heterodimeric cytokine, IL-12 protein is formed by two disulfide-linked polypeptide chains comprising p35 and p40, which are encoded by IL-12A gene and IL-12B gene, independently. And it mapped to human chromosomes 3p12-q13.2 and 5q31-33 . IL-12 cBecause of these pleiotropic activities of IL-12, dozens of molecular epidemiologic studies have explored the influences of IL-12 polymorphisms on susceptibility of various cancers, including hepatocellular carcinoma –19, coloAs the flow diagram showed Figure In the meta-analysis, we derived data from 10 studies including 4115 cancer cases and 4950 cancer-free controls for rs568408, 9 studies containing 3004 cancer cases and 3784 cancer-free controls for rs2243115, respectively.P = 0.04). However, no significant association was found after excluding one study [P > 0.05, Figure P > 0.05).The pooled analysis proved that IL-12A rs568408 polymorphisms was associated with overall cancer risk on allele comparison . The similar results were obtained after excluding studies with HWE disequilibrium .We gained 9950 patients and 11180 control subjects from 30 studies of rs3212227 polymorphism. IL-12B rs3212227 was proved to enhance overall cancer risk  and rs3212227 polymorphism . Therefore, we conducted further subgroup analyses by cancer type, ethnicity and source of control .Publication bias of the eligible studies of these IL-12 polymorphisms was accessed by funnel plot and Egger's test. The symmetrical shapes of the funnel plots Figure  and furtAttracted to the effects of IL-12 polymorphisms in the onset risk of cancer, many researchers performed numerous molecular epidemiological studies to explore the connection. Regrettably, they were failed to achieve a coincident conclusion. Existing epidemiological studies showed a higher interest on the SNP of rs3212227 in IL-12B gene, but put less focus on the rs568408 and rs2243115 SNPs of IL-12A genes. Only one meta-analysis (including eighteen studies) focused on IL-12A polymorphisms and suggested that both rs568408 and rs2243115 polymorphisms of IL-12A did not connect with cancer susceptibility . In our What we found in this meta-analysis is contrary to the previous meta-analyses , 30, ourin vitro experiments.As is depicted in introduction, IL-12 is a multiple effective cytokine that links the innate (NK cells) and acquirs (cytotoxic T lymphocytes) immune response . StructuSome possible limitations in this study need to be attended. Firstly, some potential source of heterogeneity, such as sex and environmental exposures, may have influence on the final results of the present study. Secondly, environmental factors were failed to evaluate, because lack of relevant data, such as family history, age, lifestyle, which might alter the real relation of IL-12 polymorphisms and the cancer risk. Thirdly, studies written in a third language were excluded (not in English or Chinese), thus, selection bias is inevitable. Fourthly, although we pooled all eligible publications together in our study, the sample size for some types of cancer were still small. For instance, there was only one or two literature available for cervical cancer. Thus, we should be cautious to explain our results. Finally, publication bias may exist in our meta-analysis because we could not gain the unpublished data.In conclusion, this meta-analysis draws a reliable conclusion that these IL-12 polymorphisms  might be high risk factors for cancer, which indicated IL-12 may serve as a promising marker for cancer screening. Further well-designed multi-center studies with larger sample sizes  and detailed gene-environmental interactions are warranted to confirm our findings.We obtained eligible studies prior to October 2016 from the PubMed, web of knowledge, Embase, WanFang, VIP and CNKI databases, using the terms: “cancer or carcinoma or tumor or neoplasm” and “polymorphism or variant or variation” and “interleukin-12 or IL-12”. In addition, we manually screened the references in the relevant reviews to ensure all relevant studies were not missed. Studies elected in this meta-analysis met the criteria as follows: (1) case-control studies evaluated the association of IL-12A rs568408, IL-12A rs2243115, or IL-12B rs3212227 polymorphisms with various cancer risks; (2) genotype distributions were sufficient for both cases and controls for data extraction; (3) published in English or Chinese. And we adopted following exclusion criteria: (1) repeat of previous studies, reviews, or abstracts; (2) not case-control design; (3) absence of detailed genotyping data; (4) duplication of previous data. If the overlap of data appeared in different publications, the paper included more samples were chosen.P value of controls. The subgroup analyses were performed according to cancer type, ethnicity , and source of controls. All patients in case group were confirmed by histology or pathology. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the eligible studies [Two investigators independently elected for following information from the all eligible studies: first author, publication year, cancer type, country, ethnicity, source of controls, genotyping platform, total number of cases and controls, genetic distribution among cases and controls, and Hardy–Weinberg equilibrium (HWE)  studies , The tot2 test, and it was regarded as homogeneous if P > 0.10 in Chi-square-based Q statistic. When the effects were assumed to be homogeneous, we used the fixed-effects model to assess the pooled OR. Otherwise, the random-effects model was chosen. Furthermore, source of heterogeneity among studies was explored by subgroup analyses base on cancer type, ethnicity and source of control. We adopted Begg's and Egger's test to evaluate the possible sources of bias. Sensitivity analysis was chiefly performed by orderly removing individual study and rechecked the pooled ORs to assess the stability of the final results. All statistical analyses in this study were performed by software STATA . A statistical significance was considered if P < 0.05 and all the statistics were two-sided.To evaluate the cancer risk associated IL-12 polymorphisms , we calculated ORs and 95% CI based on the genotypes in cases and controls. Five different genetic models were evaluated: (i) BB+ AB vs. AA (dominant model), (ii) BB vs. AA (homozygote model), (iii) AB vs. AA (heterozygote model), (iv) BB vs. AA+ AB (recessive model), (v) B vs. A . “A” represents the wild allele, while “B” represents the mutation allele. Heterogeneity among the studies was checked by Chi-square-based Q statistic and I


P = 0.001; recessive model, OR 1.84, 95% CI 1.13–2.98, P = 0.01; dominant model, OR 0.51, 95% CI 0.39–0.67, P < 0.001; homozygous model, OR 2.48, 95% CI 1.72–3.56, P < 0.001; heterozygous model, OR 1.67, 95% CI 1.26–2.21, P < 0.001) and in the subgroup of Asian study participants. The CA genotype at −2578C/A was a risk factor in the total population, while the CT genotype at +936C/T was a protective factor in Caucasians. None of the five genetic models suggested a significant association between −1154G/A and ovarian cancer risk in the entire study population, or between +936C/T and risk in Asian or Chinese participants. These findings should be verified in large, well-designed studies.This study meta-analyzed the literature on possible association of four polymorphisms  in the vascular endothelial growth factor (VEGF)-A gene with risk of ovarian cancer. Meta-analysis of 7 case-control studies involving +936C/T, 4 studies involving −460C/T, 4 studies involving −2578C/A and 2 studies involving −1154G/A showed significant association between −460C/T and ovarian cancer risk. This risk was observed in the total population (allelic model, OR 1.80, 95% CI 1.26–2.59,  Ovarian cancer is a major cause of cancer-related death in females worldwide , 2. AlthAngiogenesis, which refers to the formation of new capillary blood vessels from preexisting ones, is an important factor in the development and spread of cancer, including ovarian cancer –12. A keThe founding member of the VEGF family, VEGF-A, is encoded by a gene on chromosome 6p12 that comprises a 14-kb coding region of eight exons and exhibits alternate splicing to form a family of proteins. . SeveralA total of 104 potentially relevant publications published in English or Chinese up to April 12, 2017 were systematically identified in PubMed, EMBASE, Google Scholar and Chinese National Knowledge Infrastructure databases  in all but one study ..34].To be included in our review and meta-analysis, studies had to satisfy the following criteria: (1) a case-control design was used to assess the association of at least one of the four target polymorphisms with ovarian cancer risk in humans; (2) full text was available, and sufficient data were reported to estimate an odds ratio (OR) with 95% confidence interval (CI); and (3) genotype frequencies were reported. If multiple publications from the same research group appeared to report data for the same cases and controls, we included only the most recent publication in our meta-analysis.P value for HWE in controls, numbers and genotypes of cases and controls, frequencies of genotypes in cases and controls. Discrepancies were resolved by consensus.Two authors (CHX and ZHH) independently extracted the following data from included studies: first author's family name, year of publication, ethnicity, country of origin, testing methods, type of controls, The quality of the included studies was assessed independently by two authors (CHX and ZHH) according to the Newcastle–Ottawa Scale . This scZ test, with P < 0.05 defined as the significance threshold. Meta-analysis was conducted using a fixed-effect model when P > 0.10 for the Q test, indicating lack of heterogeneity among studies; otherwise, a random-effect model was used. All statistical tests for meta-analyses were performed using Review Manager 5.2 (Cochrane Collaboration). Publication bias was assessed using Begg's funnel plot Stata 14.0 , with P < 0.05 considered statistically significant.Unadjusted odds ratios (ORs) with 95% confidence intervals (95% CI) were used to assess the strength of the association of each of the four target polymorphisms with ovarian cancer risk, based on genotype frequencies in cases and controls. The significance of pooled ORs was determined using the


The association between cheese consumption and risk for major health endpoints has been investigated in many epidemiologic studies, but findings are inconsistent. As all-cause mortality can be viewed as the final net health effect of dietary intakes, we conducted a meta-analysis to examine the long-term association of cheese consumption with all-cause mortality. Relevant studies were identified by a search of the PubMed database through May 2016. Reference lists from retrieved articles were also reviewed. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using a random-effects model. Pre-specified stratified and dose-response analyses were also performed. The final analysis included nine prospective cohort studies involving 21,365 deaths. The summary RR of all-cause mortality for the highest compared with the lowest cheese consumption was 1.02 , and little evidence of heterogeneity was observed. The association between cheese consumption and risk of all-cause mortality did not significantly differ by study location, sex, age, number of events, study quality score or baseline diseases excluded. There was no dose-response relationship between cheese consumption and risk of all-cause mortality . No significant publication bias was observed. Our findings suggest that long-term cheese consumption was not associated with an increased risk of all-cause mortality. Cheese, a fermented dairy product and traditionally part of the Mediterranean diet , is consIt seems that the associations between cheese consumption and risks of multiple chronic diseases have not been totally consistent, with both positive and negative associations reported. Considering the widespread consumption of cheese, a slight reduction or increase in disease risk may represent significant public health implications. All-cause mortality is used as an indicator of safety or hazard of an intervention and can be considered as the final net influence of dietary intakes on health . FurtherThis study was conducted using a predefined protocol and in accordance with the proposed MOOSE  . A literStudies were considered eligible if they met the following criteria: (1) the study design was a prospective study; (2) relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between cheese consumption and all-cause mortality were reported.Data extraction was performed using a standardized data collection form, and the information extracted was as follows: the first author’s last name, publication year, study name, duration of follow-up, number of deaths and total participants, sex and age, quantity of intake, the most fully adjusted RRs and 95% CIs, prevalent diseases excluded at baseline, and variables adjusted for in the analysis. Data were extracted by two authors (XT and G-CC). Discrepancies were resolved by discussion and, if agreement could not be achieved, by adjudication of a third reviewer (L-QQ). A random-effects model was used to calculate summary RRs and 95% CIs for the highest compared with the lowest category of cheese consumption. RRs and corresponding SEs were logarithmically transformed to stabilize variance and normalize the distribution . For oneQ test [p < 0.1 and the I2 statistic, a quantitative measure of inconsistency across studies. To explore potential sources of heterogeneity, subgroup and meta-regression analyses were performed according to study and population characteristics including: study location, sex, age, duration of follow-up, number of events, the study quality score and baseline diseases excluded. To test the robustness of the results, a sensitivity analysis was carried out by omitting one cohort in each turn to examine the impacts of a single study on the overall effect estimate.Heterogeneity in studies was tested using the Q test  at a sigp-value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline was equal to zero. Potential publication bias was assessed with Egger’s test and Begg’s test [p values < 0.05 were considered to be statistically significant.In addition, we quantified the dose-response relationship of cheese consumption with risk of all-cause mortality based on the method proposed by Greenland and Longnecker . To perfg’s test ,17 in whn = 6) or was specific diet patterns including cheese (n = 4). Seven studies were excluded because the outcome was CVD mortality [The flow chart of the literature search is presented in ortality ,19, coroortality ,21 or stortality ,23,24 wiortality ,30,31,32The characteristics of the included studies are shown in Pheterogeneity = 0.74, I2 = 0%). There was no evidence of publication bias with Egger’s (p = 0.37) or with Begg’s test (p = 0.59).A meta-analysis of nine prospective studies yielded a summary RR of 1.02 (95% CI: 0.97–1.06) for the highest compared with the lowest cheese consumption , with nop = 0.09), with a marginally significant increased risk of all-cause mortality associated high cheese consumption among two studies with a duration of <10 years , but not among those with a duration of ≥10 years . The overall result remained stable in a sensitivity analysis in which one study at a time was omitted and the rest were analyzed, with a range from 1.00 (95% CI: 0.94–1.06) to 1.02 (95% CI: 0.97–1.08).I2 = 0%) (p for nonlinearity = 0.082)  . There w= 0.082) .In this meta-analysis, we found no significant association between cheese consumption and all-cause mortality. Such a null association was consistent in stratified analysis by a number of study and population characteristics such as sex, geographical areas, baseline disease excluded, and the study quality. Dose-response analysis also found no significant association between cheese consumption and all-cause mortality. We found limited evidence for between-study heterogeneity or publication bias, and almost all studies had high quality scores (scores ≥ 8). The finding of this meta-analysis is similar with previous meta-analysis , which fSubgroup analysis based on limited numbers of studies suggested increased risk of all-cause mortality among studies followed up for <10 years but not among those followed up for ≥10 years. The result may be explained by the fact that subjects may change their diet over time and baseline measurements would not be representative for intakes during follow-up. On the other hand, those with chronic disease such as CVD and T2DM at baseline may eat more cheese in order to have good nutrition given that cheese consumption has been reported to be inversely associated with these diseases. Unfortunately, the studies with short follow-up duration were less adjusted for dietary factors.2 and specific types of fatty acids. Evidence suggests a neutral effect of cheese consumption on blood lipids [2, which is exclusively synthesized by bacteria and present in cheese, has been shown to inhibit vascular calcification and plays an important role in preventing CVD and T2DM [Although we found no association between cheese consumption and risk of all-cause mortality, there are multiple nutrients in cheese that may contribute to health benefits, such as minerals, whey protein, vitamin Kd lipids ,35,36, wd lipids . Cheese d lipids . Vitaminand T2DM ,40,41.Cheese is also one of the major food sources of saturated fat, contributing to 7.7% of total solid fat intake . SaturatWhile dairy fat does have appreciable levels of saturated fatty acids, it is made up of nearly 400 different fatty acids, including trans-fatty acids and branched-chain fatty acids . All of These findings suggest a complexity of components in cheese. Therefore, when providing dietary recommendations on high-fat dairy or cheese, overall health effects would be more informative when comparing effects of specific components in these foods.Our study has several strengths. The present meta-analysis is based on prospective studies, so we have effectively avoided recall and selection bias. It also included multiple country-specific studies, and the total numbers of nation-specific participants and events appear reasonably robust. In addition, we conducted a further dose-response analysis to include data across different categories of exposure by converting cheese consumption from servings into a visualized unit (g/day), and therefore largely strengthened the statistical power of the analysis. Furthermore, there was little evidence of heterogeneity in the analysis. We also noticed the individual study whose characteristics differ from others, i.e., Fraser’s study, which enrolled Seventh-Day Adventists ,27. BecaSeveral limitations in this meta-analysis should be considered. First, the major potential confounders adjusted for in original studies differed and residual confounders may still exist. Second, measurement errors could affect our findings as assessment of cheese consumption largely depended on self-administered questionnaires. Third, the association with high-fat cheese or low-fat cheese was not addressed because few studies reported these findings . FinallyIn conclusion, findings of the present meta-analysis indicate that cheese consumption is not significantly associated with risk of all-cause mortality. Future large prospective studies that distinguish between high-fat and low-fat cheese are warranted.


Dose–response meta-analysis suggested a nonlinear association of chocolate consumption with all outcomes. For both CHD and stroke, there was little additional risk reduction when consuming chocolate ≥3 servings/week (one serving was defined as 30 g of chocolate). For diabetes, the peak protective effect of chocolate emerged at 2 servings/week , with no benefit observed when increasing consumption above 6 servings/week. In conclusion, chocolate intake is associated with decreased risks of CHD, stroke, and diabetes. Consuming chocolate in moderation (≤6 servings/week) may be optimal for preventing these disorders. Although epidemiological studies have examined the role of chocolate in preventing cardiometabolic disease, the results remain inconsistent. Herein, we conducted a meta-analysis of prospective studies to determine the association between chocolate intake and risk of coronary heart disease (CHD), stroke, and diabetes. A systematical search in PubMed and Embase through March 2017, together with reference scrutiny of relevant literatures, was performed to identify eligible studies. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled using random effect models. Fourteen prospective studies of primary prevention with 508,705 participants were finally included, with follow-up durations ranging from 5 to 16 years. The summary RRs for the highest versus lowest chocolate consumption were 0.90 (95% CI: 0.82–0.97;  Cardiovascular disease, including coronary heart disease (CHD) and stroke, remains the leading cause of morbidity and mortality worldwide . It was Diet is one of the key lifestyle elements involved in the prevention and control of cardiometabolic disease. Chocolate is a highly popular dietary food throughout the world, and has gained increasing attention for its potential benefits in cardiometabolic health. A number of experimental and clinical studies have indicated a protective role of chocolate against oxidative stress, inflammation, endothelial dysfunction, and atherogenesis . These sThis meta-analysis was performed in accordance with the meta-analysis of observational studies in epidemiology guideline provided in . We condTo be included, the studies should meet all of the following requirements: (1) the studies were cohort or nested case–control studies; (2) the exposure of interest was chocolate consumption, defined as consumption of any type of chocolate products ; (3) the outcomes of interest included CHD, stroke, or diabetes; (4) the risk estimates of outcomes  were provided. For studies included in the dose–response meta-analysis, the risk estimates must be reported for at least three categories of chocolate intake, and for each category, the number of cases and participants or person-years were also provided . Reviews, abstracts, and duplicates were excluded. The study selection process was performed by two independent reviewers (S.Y. and X.L.) according to the inclusion and exclusion criteria, with disagreements settled by discussion with a third reviewer (Y.J.). The main characteristics of studies were abstracted, including study author, publication year, population origin, sample size, age at inclusion, ascertainments of exposure and outcome, country, duration of follow-up, outcomes measured, adjustments in multivariate models, and the maximally adjusted risk estimates. The methodological quality of included studies was assessed according to the Newcastle–Ottawa Scale (NOS) , with thp values of <0.1 indicating significance. We also reported the heterogeneity as low, moderate-to-high, and substantial with I2 values of <25%, 25–75%, and >75%, respectively [In this study, the summary risk estimates were presented as RRs with corresponding 95% confidence intervals (CIs). We pooled the study-specific risk estimates of CHD, stroke, and diabetes for the highest versus lowest categories of chocolate consumption using random effect models. Heterogeneity among the included studies was detected by the Cochrane Q test, with ectively . Subgrouectively . Leave-oectively .To evaluate the dose–response relationship between chocolate consumption and risk of each outcome, we firstly standardized the chocolate intake levels across studies using a common measure , and one serving of chocolate was assumed to approximate 30 g of chocolate . The meap-value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to zero. We performed a two-stage random-effects dose–response meta-analysis to examine the potential nonlinear association between chocolate consumption and risk of CHD, stroke, and diabetes. In the first stage, a restricted cubic spline model with three knots at the 10th, 50th, and 90th percentiles of chocolate intake was estimated using generalized least-square regression considering the correlation within each set of published RRs, as proposed by Orsini et al. . In the p-value of <0.05 was considered as significant. All statistical analyses were performed using STATA 13.0  and R 3.2.5  software, and a two-sided A total of 829 publications were preliminarily identified, of which 182 duplicates and 605 irrelevant articles were discarded. After full-text review of the remaining 42 records, 28 studies were excluded because of failure to meet the eligibility criteria. As a consequence, 14 prospective studies ,26,27,28The main characteristics of the selected studies are summarized in I2 = 24.3%, p = 0.25). Regarding CHD subtype, the RR was 0.86 (95% CI: 0.77–0.96) for myocardial infarction. The results were consistent for studies with follow-up duration of <10 years  and for studies with follow-up duration of ≥10 years . Leave-one-out sensitivity analysis had no significant influence on the pooled results. There was no indication of publication bias from Egger’s test (p = 0.12).Six prospective studies ,22,25,27p for nonlinearity = 0.006; In the dose–response meta-analysis of five studies ,21,22,25I2 = 0%, p = 0.49). With regard to stroke subtypes, the RRs were 0.87 (95% CI: 0.78–0.96) for cerebral infarction and 0.83 (95% CI: 0.71–0.97) for hemorrhagic stroke. In the stratified analysis by gender, the RRs of total stroke were 0.87 (95% CI: 0.79–0.97) and 0.84 (95% CI: 0.74–0.94), respectively, for male and female participants (p for interaction = 0.66). Besides, the results were consistent for studies with follow-up durations of <10 years  and for studies with follow-up duration of ≥10 years . The pooled risk of total stroke was not obviously modified in the sensitivity analysis by excluding one study at a time. Egger’s test suggested the presence of publication bias (p = 0.008). After introducing the “trim and fill” method to adjust this bias, the overall risk estimate remained significant in favor of chocolate intake .Eight reports from seven studies ,23,24,27p for nonlinearity = 0.001; Seven reports from six studies ,22,23,24I2 = 60%, p = 0.03). After excluding the study by Greenberg et al. [I2 = 0%, p = 0.55), with the pooled result of the remaining studies maintaining significance . In the stratified analysis by sex, the RRs were 0.79 (95% CI: 0.65–0.96) for men and 0.92 (95% CI: 0.72–1.17) for women (p for interaction = 0.34). Similarly, the risks of diabetes were not different between subsets of studies with follow-up durations of below or over 10 years (p for interaction = 0.51). Exclusion of single studies in sequence did not alter the inverse association between chocolate intake and risk of diabetes. There was an indication of publication bias from Egger’s test (p = 0.001); the summary risk estimate was marginally significant after the use of “trim and fill” method .Six independent reports from five studies ,20,26,28g et al. , the hetp for nonlinearity < 0.001; In dose–response meta-analysis of the six reports, we observed a curvilinear association between chocolate intake and risk of diabetes  is associated with a decreased risk of diabetes, while a higher than moderate intake cannot provide such a benefit. This dose–response pattern was also identified in a recent meta-analysis, which showed that light-to-moderate—but not high—consumption of chocolate has a protective role against heart failure, an end stage of cardiac disease . For CHDSome limitations should be acknowledged. First of all, recall and selection biases may be present in our study due to the observational nature of individual studies. Nevertheless, we included only studies with a prospective design and pooled the maximally-adjusted risk estimates, which greatly reduced the probability of these biases. Second, due to the lack of data, we cannot conduct stratified analyses by some important confounders, such as total energy intake, body mass index, and types of chocolate products . Third, dietary habits may also affect our final results. Subjects eating less chocolate are likely to have healthier dietary habits than those consuming chocolate in higher amounts. However, only few dietary factors were controlled for in the multivariate models of the original studies. Fourth, generalization of our findings is hampered by the geographical origin of the included studies, as they were mainly conducted in Europe and the United States.Taken together, the present meta-analysis suggests that chocolate consumption confers reduced risks of CHD, stroke, and diabetes. Consuming chocolate in moderation (1–6 servings/week) may be optimal for the prevention of these burdensome diseases. Additional large prospective studies are required to confirm the observed benefits of chocolate in populations with different characteristics and to establish the optimum frequency of chocolate intake for preventing cardiometabolic disease.


Accumulating evidences have demonstrated that lipopolysaccharide (LPS) represents the important etiologic factor for sepsis. Some previous studies have reported the relationship between common polymorphisms rs4986790 and rs4986791 in the coding gene for this receptor and the susceptibility to sepsis, but there were distinct divergences between those findings. We therefore designed this meta-analysis incorporated 28 published articles containing 6,537 sepsis patients and 8,832 controls for a more comprehensive conclusion on this matter. Odds ratios (ORs) and 95% confidence interval (95% CIs) were calculated to evaluate the association of toll like receptor 4 gene polymorphisms rs4986790 and rs4986791 with sepsis risk. Heterogeneity between included studies was inspected using Q test, and sensitivity analysis was implemented via sequential deletion of each included study to investigate the stability of overall estimates. Funnel plot and Egger’s test were adopted to examine publication bias across selected studies. We found no significant association for either the polymorphism rs4986790 or rs4986791 with sepsis susceptibility in total analysis under any genetic models. Neither did we after combining these two polymorphisms. The results of this meta-analysis suggest that the rs4986790 and rs4986791 polymorphisms in toll like receptor 4 gene may have no statistically significant influence on sepsis susceptibility. Sepsis is a systemic inflammatory response syndrome (SIRS) induced by organism infections from pathogenic microorganisms457et al. indicated that apart from the polymorphism rs4986790, another one rs4986791  in this gene was also related to the severity of post-traumatic sepsiset al. showed that there were no obvious association between polymorphisms in the gene toll like receptor 4 and sepsis caused by gram negative bacteria in their studyet al. found that the morbidity and mortality rate of sepsis didn’t correlate with toll like receptor 4 gene mutations in their study on postoperative sepsis induced by various microorganism infectionsInnate immune system depends on pattern recognition receptors (PRRs) to detect conserved structures of pathogenic microorganisms , which are called pathogen-associated molecular patterns (PAMPs)12It is important in terms of clinical value and theoretical significance to get clearer perspective on the relationship of toll like receptor 4 gene polymorphisms rs4986790 and rs4986791 with sepsis risk. Consequently, we systematically analyzed this correlation via the method of meta-analysis in this study.TLR4”, “polymorphism or mutation or variant” and “sepsis”. What’s more, we also searched for additional articles through manually screening the reference lists of relevant articles or reviews to minimize the possibility of missing potent papers. Eligible studies were enrolled in this meta-analysis based on the following criteria: they estimated the correlation of the rs4986790 and/or rs4986791 polymorphisms in toll like receptor 4 gene with sepsis and had a case-control design; they adopted valid genotyping method; and they provided information about genotype distribution in case and control group for calculating pooled odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs). Meanwhile, publications were excluded if they were case-only studies, with irrelevant title or abstract, without sufficient genotype data or focusing on animals.We searched potentially relevant studies from MEDLINE, EMBASE, Google Scholar and CNKI up to January 2016. The key terms adopted in search strategy included “toll like receptor 4 or P values for Hardy-Weinberg equilibrium (HWE) in control group. All disagreements over extracted data were resolved through discussion between the two investigators to reach a consensus.The following information were extracted by two investigators from included articles: the first author’s name, publication year, original country, ethnicity, control source, genotyping method, numbers of cases and controls, genotype frequency and 2-based Q test. The fixed-effect model was adopted to calculate the pooled ORs when P > 0.05 in Q test which indicated the lack of heterogeneity; otherwise, the random-effect model was selected. HWE was checked in the control group via χ2 test. Publication bias was examined with Begg’s funnel plot and Egger’s test. Sensitivity analysis was performed to reflect the effect of each individual dataset on pooled results through sequentially omitting each included study. Statistical analysis was conducted using STATA version 12.0 (STATA Corp). P < 0.05 was considered statistically significant for all tests.The ORs and 95% CIs were calculated to assess the association of sepsis susceptibility with toll like receptor 4 rs4986790 polymorphism under five genetic models: GG vs. AA, GG + GA vs. AA, GG vs. GA+AA, allele G vs. allele A, and GA vs. GG, as well as with the polymorphism rs4986791 under the five genetic models: TT vs. CC, TT+CT vs. CC, TT vs. CC+CT, allele T vs. allele C and CT vs. CC. In addition, subgroup analysis was implemented according to ethnicity. Between-study heterogeneity was evaluated through the χ2 test, genotype distributions in controls were consistent with HWE in all studies for the polymorphism rs4986791 ; while such distributions deviated from HWE expectation in two studies from the report by Tellería-Orriols et al.P = 0.0001), and perfectly fit in with the expectation in the other studies with P values ranging from 0.1690 to 0.9620.According to the search strategy, 277 potentially relevant studies were initially identified from MEDLINE, EMBASE, Google Scholar and CNKI, and 163 of them were exclude due to irrelevant titles or abstracts. Additionally, consequent screening removed 86 more reports for not concerning on the association between the polymorphism rs4986790 or rs4986791 of toll like receptor 4 and sepsis (71) and insufficient data (15). Therefore, as showed in 131416171819202122232425262728293031323334353637383940In total analysis, the polymorphism rs4986790 of toll like receptor 4 gene showed no significant association with sepsis susceptibility under genetic models GG vs. AA  , GG + AGAs for the polymorphism rs4986791, no significant influence thereof was detected in total analysis under the contrasts of TT vs. CC , TT + CTIn addition, we also examined possible effects of the combination between the polymorphisms rs4986790 and rs4986791 on the sepsis onset. As a result, the combination of these two polymorphism still lacked significant impact on the disease risk under homozygous model  , dominanP = 0.001; P < 0.001; P = 0.002) as well as for the polymorphism rs4986791 under TT + CT vs. CC, allele T vs. allele C and CT vs. CC contrasts , thus the random-effects model was applied to calculate pooled ORs in these cases. As for the other comparisons, the fixed-effects model was utilized considering the absence of significant heterogeneity .Significant heterogeneity was observed for the polymorphism rs4986790 under GG + GA vs. AA model, allele G vs. allele A model and GA vs. GG model  in view of the existence of significant heterogeneity, and pooled with the fixed-effects model under the homozygous and recessive models  because of the lack of significant heterogeneity.As for the OR values for the effects of the combination between the two polymorphism, they were summarized applying the random-effects model under the dominant, allele and heterozygous models (P = 0.674).We implemented sensitivity analysis to evaluate the stability of pooled results. We excluded each study one by one and observed that no pooled ORs was substantially affected , implyinSepsis is caused by infections and characterized by acute onset, rapid progression and high fatality rate, being a common postoperative complication of severe traumas and burns. SIRS may develop to septic stock and multiple organ dysfunction syndrome (MODS), and studies on SIRS, sepsis, severe sepsis, septic stock and MODS indicate significant differences in different individuals. Specifically, inflammatory responses may develop easily in some people, which is difficult to be controlled and then become MODS, while different results may occur in other people with the same SIRS. Moreover, people with similar SIRS or sepsis can show different prognosis when they adopt same therapeutic measures. All these evidence indicate that sepsis is affected by genetic factors as well. Therefore, it’s important to explore the roles of sepsis-related genes, which provides theoretical basis to understand sepsis pathogenesis.et al. in 1997TLRs, a group of main PRRs, can recognize pathogenic microorganisms through PAMPs, activate intracellular signal transduction pathways and induce the generation of innate immunity. Therefore, TLRs are involved in the pathogenic courses of numerous diseases and closely correlated with communicable diseases, tumors, cardiovascular diseases, autoimmune diseases and allergy. According to their positions in chromosome, genetic structures and amino acid sequences, 11 members of TLRs family are divided to 5 subfamilies. Among members in this family, toll like receptor 4, first found and reported by Medzhitov et al. found that the polymorphism T-2242C in toll like receptor 4 gene might be related to higher sepsis morbidity rate and organ dysfunctionet al. put forward in their study that the polymorphism rs11536889 in this gene was associated with renal, coagulation and hepatic organ failure in sepsis patientset al. reported that the polymorphism rs4986790 might shorten the time-to-onset of severe sepsis or septic shock in patients permitted to intensive care unitset al., the polymorphism rs4986790 was demonstrated to be involved in the severity of SIRSFor example, Chen et al. in 2012Considering those discrepancies, we performed this meta-analysis to comprehensively analyze the associations of the rs4986790 and rs4986791 polymorphisms in toll like receptor 4 gene with sepsis susceptibility involving 51 relevant case-control studies. The results of this study showed that our studied polymorphisms, overall, had no significant association with the susceptibility of sepsis, but that both polymorphisms were related to increased risk of developing sepsis in other-ethnicity subgroups under corresponding genetic models after stratified analysis by ethnicity. Based on 6,537 sepsis patients and 8,832 controls, our findings had certain reliability, and sensitivity analysis also verified their stability. Compared to the previous individual case-control studies, our meta-analysis had a larger sample size and a more detailed stratification analysis by ethnicity, so our results were more reliable and comprehensive. In a recent meta-analysis about rs4986790 polymorphsism and sepsis susceptibility published by Zhu In conclusion, the results of this meta-analysis showed that toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms might not have independent association with sepsis susceptibility. In view of the advantages and disadvantages in this meta-analysis, the results should be further verified by better-designed studies based on larger sample size and more consideration of gene-gene and gene-environment interactions.How to cite this article: Liu, R. et al. The relationship between toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms and sepsis susceptibility: A meta-analysis. Sci. Rep.6, 38947; doi: 10.1038/srep38947 (2016).Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.