Variation of TaMyb10 and their function on grain color and pre-harvest sprouting resistance of wheat.

Pre-harvest sprouting (PHS) is a significant threat to global food security due to its association with losses in both yield and quality. Among the genes involved in PHS resistance in wheat, PHS-3D (TaMyb10-D) plays a crucial role. Here, we characterized the sequence variations of TaMyb10 genes in 416 bread wheat and 302 Aegilops tauschii accessions. Within TaMyb10-A sequences, we identified a deletion ranging from 214 to 305 bp in the signal and amino acid coding region, present in 61.3% of the accessions. Similarly, 79.3% of the TaMyb10-B sequences within the third exon region exhibited a 19 bp deletion. Additionally, 40.8% of the accessions lacked the 2.4 Mb fragment (in/del mutations) on Chr3D, where TaMyb10-D/PHS-3D was located. Interestingly, the geographical distribution of accessions showed little correlation with the divergence of TaMyb10. TaMyb10-A-IIIDele, TaMyb10-B-IVDele, and TaMyb10-D-VDele genotypes were prevalent in wheat populations across continents. Despite their structural variations, the five distinct protein types exhibited comparable ability to bind the promoters of downstream genes in the flavonoid and ABA pathways, such as CHS, DFR, and NCED. Furthermore, the combination of TaMyb10 homologs was significantly associated with grain color and germination percentages. Accessions exclusively harboring TaMyb10-D displayed red seed color and reduced germination percentages, indicating the predominant role of TaMyb10-D compared to TaMyb10-A and TaMyb10-B. This comprehensive investigation enhances our understanding of the structural variations and functional divergence of TaMyb10, providing valuable insights and resources for improving PHS resistance in wheat.

Identification of candidate gene for the defective kernel phenotype using bulked segregant RNA and exome capture sequencing methods in wheat.

Wheat is a significant source of protein and starch worldwide. The defective kernel (Dek) mutant AK-3537, displaying a large hollow area in the endosperm and shrunken grain, was obtained through ethyl methane sulfonate (EMS) treatment of the wheat cultivar Aikang 58 (AK58). The mode of inheritance of the AK-3537 grain Dek phenotype was determined to be recessive with a specific statistical significance level. We used bulked segregant RNA-seq (BSR-seq), BSA-based exome capture sequencing (BSE-seq), and the ΔSNP-index algorithm to identify candidate regions for the grain Dek phenotype. Two major candidate regions, DCR1 (Dek candidate region 1) and DCR2, were identified on chromosome 7A between 279.98 and 287.93 Mb and 565.34 and 568.59 Mb, respectively. Based on transcriptome analysis and previous reports, we designed KASP genotyping assays based on SNP variations in the candidate regions and speculated that the candidate gene is TraesCS7A03G0625900 (HMGS-7A), which encodes a 3-hydroxy-3-methylglutaryl-CoA synthase. One SNP variation located at position 1,049 in the coding sequence (G>A) causes an amino acid change from Gly to Asp. The research suggests that functional changes in HMGS-7A may affect the expression of key enzyme genes involved in wheat starch syntheses, such as GBSSII and SSIIIa.

Four new species of Ditrigona Moore (Lepidoptera, Drepanidae) in China and an annotated catalogue.

The Chinese species of the genus Ditrigona Moore, 1888 are reviewed and an annotated catalogue is provided. Four new species are described from China: Ditrigonasinespina Jiang & Han, sp. nov., Ditrigonaparva Jiang & Han, sp. nov., Ditrigonaconcava Guo & Han, sp. nov., and Ditrigonafusca Guo & Han, sp. nov. Derocacrystalla Chu & Wang, 1987 and Auzatellapentesticha Chu & Wang, 1987 are newly combined into, respectively, the derocina and quinaria species groups of Ditrigona. Ditrigonadiana Wilkinson is newly recorded in China. This results in 43 species of Ditrigona for the fauna of China. Illustrations of habitus and genitalia of the new species and most known species are presented.

The PGS1 basic helix-loop-helix protein regulates Fl3 to impact seed growth and grain yield in cereals.

Plant transcription factors (TFs), such as basic helix-loop-helix (bHLH) and AT-rich zinc-binding proteins (PLATZ), play critical roles in regulating the expression of developmental genes in cereals. We identified the bHLH protein TaPGS1 (T. aestivum Positive Regulator of Grain Size 1) specifically expressed in the seeds at 5-20 days post-anthesis in wheat. TaPGS1 was ectopically overexpressed (OE) in wheat and rice, leading to increased grain weight (up to 13.81% in wheat and 18.55% in rice lines) and grain size. Carbohydrate and total protein levels also increased. Scanning electron microscopy results indicated that the starch granules in the endosperm of TaPGS1 OE wheat and rice lines were smaller and tightly embedded in a proteinaceous matrix. Furthermore, TaPGS1 was bound directly to the E-box motif at the promoter of the PLATZ TF genes TaFl3 and OsFl3 and positively regulated their expression in wheat and rice. In rice, the OsFl3 CRISPR/Cas9 knockout lines showed reduced average thousand-grain weight, grain width, and grain length in rice. Our results reveal that TaPGS1 functions as a valuable trait-associated gene for improving cereal grain yield.

Effect of ondansetron on reducing ICU mortality in patients with acute kidney injury.

The purpose of this study is to identify medications with potentially beneficial effects on decreasing mortality in patients with acute kidney injury (AKI) while in the intensive care unit (ICU). We used logistic regression to investigate associations between medications received and ICU mortality in patients with AKI in the MIMIC III database. Drugs associated with reduced mortality were then validated using the eICU database. Propensity score matching (PSM) was used for matching the patients' baseline severity of illness followed by a chi-square test to calculate the significance of drug use and mortality. Finally, we examined gene expression signatures to explore the drug's molecular mechanism on AKI. While several drugs demonstrated potential beneficial effects on reducing mortality, most were used for potentially fatal illnesses (e.g. antibiotics, cardiac medications). One exception was found, ondansetron, a drug without previously identified life-saving effects, has correlation with lower mortality among AKI patients. This association was confirmed in a subsequent analysis using the eICU database. Based on the comparison of gene expression signatures, the presumed therapeutic effect of ondansetron may be elicited through the NF-KB pathway and JAK-STAT pathway. Our findings provide real-world evidence to support clinical trials of ondansetron for treatment of AKI.

An Emulation of Randomized Trials of Administrating Antipsychotics in PTSD Patients for Outcomes of Suicide-Related Events.

Post-traumatic stress disorder (PTSD) is a prevalent mental disorder marked by psychological and behavioral changes. Currently, there is no consensus of preferred antipsychotics to be used for the treatment of PTSD. We aim to discover whether certain antipsychotics have decreased suicide risk in the PTSD population, as these patients may be at higher risk. A total of 38,807 patients were identified with a diagnosis of PTSD through the ICD9 or ICD10 codes from January 2004 to October 2019. An emulation of randomized clinical trials was conducted to compare the outcomes of suicide-related events (SREs) among PTSD patients who ever used one of eight individual antipsychotics after the diagnosis of PTSD. Exclusion criteria included patients with a history of SREs and a previous history of antipsychotic use within one year before enrollment. Eligible individuals were assigned to a treatment group according to the antipsychotic initiated and followed until stopping current treatment, switching to another same class of drugs, death, or loss to follow up. The primary outcome was to identify the frequency of SREs associated with each antipsychotic. SREs were defined as ideation, attempts, and death by suicide. Pooled logistic regression methods with the Firth option were conducted to compare two drugs for their outcomes using SAS version 9.4 (SAS Institute, Cary, NC, USA). The results were adjusted for baseline characteristics and post-baseline, time-varying confounders. A total of 5294 patients were eligible for enrollment with an average follow up of 7.86 months. A total of 157 SREs were recorded throughout this study. Lurasidone showed a statistically significant decrease in SREs when compared head to head to almost all the other antipsychotics: aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (p < 0.0001 and false discovery rate-adjusted p value < 0.0004). In addition, olanzapine was associated with higher SREs than quetiapine and risperidone, and ziprasidone was associated with higher SREs than risperidone. The results of this study suggest that certain antipsychotics may put individuals within the PTSD population at an increased risk of SREs, and that careful consideration may need to be taken when prescribed.

Myb10-D confers PHS-3D resistance to pre-harvest sprouting by regulating NCED in ABA biosynthesis pathway of wheat.

Pre-harvest sprouting (PHS), the germination of grain before harvest, is a serious problem resulting in wheat yield and quality losses. Here, we mapped the PHS resistance gene PHS-3D from synthetic hexaploid wheat to a 2.4 Mb presence-absence variation (PAV) region and found that its resistance effect was attributed to the pleiotropic Myb10-D by integrated omics and functional analyses. Three haplotypes were detected in this PAV region among 262 worldwide wheat lines and 16 Aegilops tauschii, and the germination percentages of wheat lines containing Myb10-D was approximately 40% lower than that of the other lines. Transcriptome and metabolome profiling indicated that Myb10-D affected the transcription of genes in both the flavonoid and abscisic acid (ABA) biosynthesis pathways, which resulted in increases in flavonoids and ABA in transgenic wheat lines. Myb10-D activates 9-cis-epoxycarotenoid dioxygenase (NCED) by biding the secondary wall MYB-responsive element (SMRE) to promote ABA biosynthesis in early wheat seed development stages. We revealed that the newly discovered function of Myb10-D confers PHS resistance by enhancing ABA biosynthesis to delay germination in wheat. The PAV harboring Myb10-D associated with grain color and PHS will be useful for understanding and selecting white grained PHS resistant wheat cultivars.

Identification and Characterization of PLATZ Transcription Factors in Wheat.

The PLATZ (plant AT-rich protein and zinc-binding protein) transcription factor family is a class of plant-specific zinc-dependent DNA-binding proteins. PLATZ has essential roles in seed endosperm development, as well as promoting cell proliferation duration in the earlier stages of the crops. In the present study, 62 TaPLATZ genes were identified from the wheat genome, and they were unequally distributed on 15 chromosomes. According to the phylogenetic analysis, 62 TaPLATZ genes were classified into six groups, including two groups that were unique in wheat. Members in the same groups shared similar exon-intron structures. The polyploidization, together with genome duplication of wheat, plays a crucial role in the expansion of the TaPLATZs family. Transcriptome data indicated a distinct divergence expression pattern of TaPLATZ genes that could be clustered into four modules. The TaPLATZs in Module b possessed a seed-specific expression pattern and displayed obvious high expression in the earlier development stage of seeds. Subcellular localization data of TaPLATZs suggesting that they likely perform a function as a conventional transcription factor. This study provides insight into understanding the structure divergence, evolutionary features, expression profiles, and potential function of PLATZ in wheat.

An Emulation of Randomized Trials of Administrating Benzodiazepines in PTSD Patients for Outcomes of Suicide-Related Events.

Benzodiazepines is a class of medications frequently prescribed to patients with post-traumatic stress disorder. Patients with PTSD have a notable increased risk of suicide compared to the general population. These medications have been theorized to increase suicidality and pose a risk when used in this patient population. Previous research has found little utility of using benzodiazepines in the PTSD population. However, benzodiazepines are still commonly prescribed by some clinicians for their symptomatic benefit. This study aims to identify the comparative efficacy of commonly prescribed benzodiazepines including midazolam, lorazepam, alprazolam, clonazepam, diazepam and temazepam in relation to suicide-related behaviors (SRBs). A total of 38,807 patients who had an ICD9 or ICD10 diagnosis of PTSD from January 2004 to October 2019 were identified through an electronic medical record database. Inclusion criteria include patients that initiated one of the above benzodiazepines after PTSD diagnosis. Exclusion criteria include previous history of benzodiazepine usage or history of SRBs within the last year prior to enrollment. For patients enrolled in this study, other concomitant drugs were not limited. The primary outcome was onset of SRBs with each respective benzodiazepine. SRBs were identified as ideation, attempt, or death from suicide. We emulated clinical trials of head-to-head comparison between two drugs by pooled logistic regression methods with the Firth option adjusting for baseline characteristics and post-baseline confounders. A total of 5753 patients were eligible for this study, with an average follow up of 5.82 months. The overall incidence for SRB was 1.51% (87/5753). Head-to-head comparisons identified that patients who received alprazolam had fewer SRBs compared to clonazepam (p = 0.0351) and lorazepam (p = 0.0373), and patients taking midazolam experienced fewer relative incidences of SRBs when compared to lorazepam (p = 0.0021) and clonazepam (p = 0.0297). After adjusting for the false discovery rate (FDR), midazolam still had fewer SRBs compared to lorazepam (FDR-adjusted p value = 0.0315). Certain benzodiazepines may provide a reduced risk of development of SRBs, suggesting careful consideration when prescribing benzodiazepines to the PTSD population.

Prediction of Suicide-Related Events by Analyzing Electronic Medical Records from PTSD Patients with Bipolar Disorder.

Around 800,000 people worldwide die from suicide every year and it's the 10th leading cause of death in the US. It is of great value to build a mathematic model that can accurately predict suicide especially in high-risk populations. Several different ML-based models were trained and evaluated using features obtained from electronic medical records (EMRs). The contribution of each feature was calculated to determine how it impacted the model predictions. The best-performing model was selected for analysis and decomposition. Random forest showed the best performance with true positive rates (TPR) and positive predictive values (PPV) of greater than 80%. The use of Sertraline, Fentanyl, Aripiprazole, Lamotrigine, and Tramadol were strong indicators for no SREs within one year. The use of Haloperidol, Trazodone and Citalopram, a diagnosis of autistic disorder, schizophrenic disorder, or substance use disorder at the time of a diagnosis of both PTSD and bipolar disorder, predicted the onset of SREs within one year. The use of Trazodone and Citalopram at baseline predicted the onset of SREs within one year. Additional features with potential protective or hazardous effects for SREs were identified by the model. We constructed an ML-based model that was successful in identifying patients in a subpopulation at high-risk for SREs within a year of diagnosis of both PTSD and bipolar disorder. The model also provides feature decompositions to guide mechanism studies. The validation of this model with additional EMR datasets will be of great value in resource allocation and clinical decision making.

The Performance of Gene Expression Signature-Guided Drug-Disease Association in Different Categories of Drugs and Diseases.

A gene expression signature (GES) is a group of genes that shows a unique expression profile as a result of perturbations by drugs, genetic modification or diseases on the transcriptional machinery. The comparisons between GES profiles have been used to investigate the relationships between drugs, their targets and diseases with quite a few successful cases reported. Especially in the study of GES-guided drugs-disease associations, researchers believe that if a GES induced by a drug is opposite to a GES induced by a disease, the drug may have potential as a treatment of that disease. In this study, we data-mined the crowd extracted expression of differential signatures (CREEDS) database to evaluate the similarity between GES profiles from drugs and their indicated diseases. Our study aims to explore the application domains of GES-guided drug-disease associations through the analysis of the similarity of GES profiles on known pairs of drug-disease associations, thereby identifying subgroups of drugs/diseases that are suitable for GES-guided drug repositioning approaches. Our results supported our hypothesis that the GES-guided drug-disease association method is better suited for some subgroups or pathways such as drugs and diseases associated with the immune system, diseases of the nervous system, non-chemotherapy drugs or the mTOR signaling pathway.

Aureochaeglobosins A-C, Three [4 + 2] Adducts of Chaetoglobosin and Aureonitol Derivatives from Chaetomium globosum.

Aureochaeglobosins A-C (1-3), three novel [4 + 2] cycloaddition heterodimers of chaetoglobosin and aureonitol derivatives, were obtained from the culture of endophytic fungus Chaetomium globosum, representing the first adduct examples of chaetoglobosins. Their structures were elucidated by extensive spectroscopic analyses, single-crystal X-ray diffraction, and a modified Mosher's method. Compounds 2 and 3 showed significant cytotoxicities against human MDA-MB-231 cancer cells with IC50 values of 7.6 and 10.8 µM, respectively.

Global identification, structural analysis and expression characterization of bHLH transcription factors in wheat.

BACKGROUND: Basic helix-loop-helix (bHLH) transcription factors (TFs), which are widely distributed in eukaryotic organisms, play crucial roles in plant development. However, no comprehensive analysis of the bHLH family in wheat (Triticum aestivum L.) has been undertaken previously. RESULTS: In this study, 225 bHLH TFs predicted from wheat using genomic and RNA sequencing data were subjected to identification, classification, phylogenetic reconstruction, conserved motif characterization, chromosomal distribution determination and expression pattern analysis. One basic region, two helix regions and one loop region were found to be conserved in wheat bHLH TFs. The bHLH proteins could be separated into four categories based on sequences in their basic regions. Neighbor-joining-based phylogenetic analysis of conserved bHLH domains from wheat, Arabidopsis and rice identified 26 subfamilies of bHLH TFs, of which 23 were found in wheat. A total of 82 wheat bHLH genes had orthologs in Arabidopsis (27 TFs), rice (28 TFs) and both of them (27 TFs). Seven tissue-specific bHLH TF clusters were identified according to their expression patterns in endosperm, aleurone, seedlings, heading-stage spikes, flag leaves, shoots and roots. Expression levels of six endosperm-specifically expressed TFs measured by qPCR and RNA-seq showed a good correlation. CONCLUSION: The 225 bHLH transcription factors identified from wheat could be classed into 23 subfamilies, and those members from the same subfamily with similar sequence motifs generally have similar expression patterns.

Identification and positional distribution analysis of transcription factor binding sites for genes from the wheat fl-cDNA sequences.

The binding sites of transcription factors (TFs) in upstream DNA regions are called transcription factor binding sites (TFBSs). TFBSs are important elements for regulating gene expression. To date, there have been few studies on the profiles of TFBSs in plants. In total, 4,873 sequences with 5' upstream regions from 8530 wheat fl-cDNA sequences were used to predict TFBSs. We found 4572 TFBSs for the MADS TF family, which was twice as many as for bHLH (1951), B3 (1951), HB superfamily (1914), ERF (1820), and AP2/ERF (1725) TFs, and was approximately four times higher than the remaining TFBS types. The percentage of TFBSs and TF members showed a distinct distribution in different tissues. Overall, the distribution of TFBSs in the upstream regions of wheat fl-cDNA sequences had significant difference. Meanwhile, high frequencies of some types of TFBSs were found in specific regions in the upstream sequences. Both TFs and fl-cDNA with TFBSs predicted in the same tissues exhibited specific distribution preferences for regulating gene expression. The tissue-specific analysis of TFs and fl-cDNA with TFBSs provides useful information for functional research, and can be used to identify relationships between tissue-specific TFs and fl-cDNA with TFBSs. Moreover, the positional distribution of TFBSs indicates that some types of wheat TFBS have different positional distribution preferences in the upstream regions of genes.

Chemical constituents from Phyllanthus emblica and the cytoprotective effects on H2O2-induced PC12 cell injuries.

Two new compounds (1-2), including a bisabolane-type sesquiterpenoid (1), one new diphenyl ether derivative (2), together with 23 known compounds (3-25), were isolated from the fruits of Phyllanthus emblica. Their structures were elucidated by detailed spectroscopic analysis. All the isolated compounds were screened for the DPPH scavenging effects and cytoprotective effects against H2O2 induced PC12 cells injury. Compounds 12-15 showed significant DPPH scavenging effects with the IC50 values in the range of 3.25-4.18 µM. Among these potential antioxidants, compound 14 improved the survival of PC12 cells after H2O2 exposure without showing any cytotoxicity at the tested concentrations.

Significant association of alpha-methylacyl-CoA racemase gene polymorphisms with susceptibility to prostate cancer: a meta-analysis.

BACKGROUND: Alpha-methylacyl-CoA racemase(AMACR) is thought to play key roles in diagnosis and prognosis of prostate cancer. However, studies of associations between AMACR gene polymorphisms and prostate cancer risk reported inconsistent results. Therefore, we conducted the present meta-analysis to clarify the link between AMACR gene polymorphisms and prostate cancer risk. MATERIALS AND METHODS: A literature search was performed in PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang and Weipu databases. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to assess the strength of any association between AMACR polymorphisms and prostate cancer risk. Subgroup analyses by ethnicity, source of controls, quality control and sample size were also conducted. RESULTS: Five studies covering 3,313 cases and 3,676 controls on five polymorphisms (D175G, M9V, S201L, K277E and Q239H) were included in this meta-analysis. Significant associations were detected between prostate cancer and D175G (dominant model: OR=0.89, 95%CI=0.80-0.99, P=0.04) and M9V (dominant model: OR=0.87, 95%CI=0.78-0.97, P=0.01) polymorphisms as well as that in subgroup analyses. We also observed significant decreased prostate cancer risk in the dominant model (OR=0.90, 95%CI=0.81-0.99, P=0.04) for the S201L polymorphism. However, K277E and Q239H polymorphisms did not appear to be related to prostate cancer risk. CONCLUSIONS: The current meta- analysis indicated that D175G and M9V polymorphisms of the AMACR gene are related to prostate cancer. The S201L polymorphism might also be linked with prostate cancer risk to some extent. However, no association was observed between K277E or Q239H polymorphisms and susceptibility to prostate cancer.

Genome-wide characterization of developmental stage- and tissue-specific transcription factors in wheat.

BACKGROUND: Wheat (Triticum aestivum) is one of the most important cereal crops, providing food for humans and feed for other animals. However, its productivity is challenged by various biotic and abiotic stresses such as fungal diseases, insects, drought, salinity, and cold. Transcription factors (TFs) regulate gene expression in different tissues and at various developmental stages in plants and animals, and they can be identified and classified into families according to their structural and specialized DNA-binding domains (DBDs). Transcription factors are important regulatory components of the genome, and are the main targets for engineering stress tolerance. RESULTS: In total, 2407 putative TFs were identified from wheat expressed sequence tags, and then classified into 63 families by using Hmm searches against hidden Markov model (HMM) profiles. In this study, 2407 TFs represented approximately 2.22% of all genes in the wheat genome, a smaller proportion than those reported for other cereals in PlantTFDB V3.0 (3.33%-5.86%) and PlnTFDB (4.30%-6.46%). We assembled information from the various databases for individual TFs, including annotations and details of their developmental stage- and tissue-specific expression patterns. Based on this information, we identified 1257 developmental stage-specific TFs and 1104 tissue-specific TFs, accounting for 52.22% and 45.87% of the 2407 wheat TFs, respectively. We identified 338, 269, 262, 175, 49, and 18 tissue-specific TFs in the flower, seed, root, leaf, stem, and crown, respectively. There were 100, 6, 342, 141, 390, and 278 TFs specifically expressed at the dormant seed, germinating seed, reproductive, ripening, seedling, and vegetative stages, respectively. We constructed a comprehensive database of wheat TFs, designated as WheatTFDB ( http://xms.sicau.edu.cn/wheatTFDB/ ). CONCLUSIONS: Approximately 2.22% (2407 genes) of all genes in the wheat genome were identified as TFs, and were clustered into 63 TF families. We identified 1257 developmental stage-specific TFs and 1104 tissue-specific TFs, based on information about their developmental- and tissue-specific expression patterns obtained from publicly available gene expression databases. The 2407 wheat TFs and their annotations are summarized in our database, WheatTFDB. These data will be useful identifying target TFs involved in the stress response at a particular stage of development.

Angiotensin-converting enzyme insertion/deletion polymorphism and gastric cancer: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Several studies were launched to investigate the potential function of ACE I/D polymorphism in gastric cancer development and prognosis, but no conclusive results have been obtained. We conducted a systematic review and meta-analysis to evaluate the association between ACE I/D polymorphism and gastric cancer. METHODS: A systemic search was performed in PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang and Weipu databases (until October 15,2013) to identify all published records on association between the ACE I/D polymorphism and gastric cancer. We adopted the odds ratio (OR) and 95% confidence interval (95%CI) as measure of effect. Meta-analysis was conducted using fixed/random-effects model in STATA 12.0. RESULTS: Eventually a total of seven studies with 1392 cases and 2951 controls were included in our meta-analysis. No association was detected between ACE I/D polymorphism and gastric cancer susceptibility (DI+DD vs II: OR=1.06, 95%CI=0.92-1.21, P=0.443). However, we found that the DD genotype was significantly associated with increased lymph node metastasis (DD vs DI+II: OR=3.48, CI=1.77-6.85, P<0.001), and more advanced clinical stage (DD vs DI+II: OR=2.43, CI=1.34-4.39, P=0.003) of gastric cancer. CONCLUSION: Our results indicated that ACE I/D polymorphism could not be directly associated with gastric cancer susceptibility, but might play important role in gastric cancer prognosis. Future studies with larger sample size are warranted for further evaluation.

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: a meta-analysis.

INTRODUCTION: The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies. MATERIALS AND METHODS: A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6(th) 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0. RESULTS: A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR=1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR=1.60, 95%CI: 1.24-2.06, P=0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR=2.08, 95%CI: 1.29-3.35, P=0.003) and Caucasians (dominant model: OR=1.31, 95%CI: 1.10-1.56, P=0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR=1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery. CONCLUSION: Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders.