Open a new epoch of arsenic trioxide investigation: ATOdb.

Arsenic trioxide (ATO) is a great discovery in the treatment of acute promyelocytic leukemia (APL), which has been used in an increasing number of malignant diseases. Systematic integrative analysis will help to precisely understand the mechanism of ATO and find new combined drugs. Therefore, we developed a one-stop comprehensive database of ATO named ATOdb by manually compiling a wealth of experimentally supported ATO-related data from 3479 articles, and integrated analysis tools. The current version of ATOdb contains 8373 associations among 2300 ATO targets, 80 conditions and 262 combined drugs. Each entry in ATOdb contains detailed information on ATO targets, therapeutic/side effects, systems, cell names, cell types, regulations, detection methods, brief descriptions, references, etc. Furthermore, ATOdb also provides data visualization and analysis results such as the drug similarities, protein-protein interactions, and miRNA-mRNA relationships. An easy-to-use web interface was deployed in ATOdb for users to easily browse, search and download the data. In conclusion, ATOdb will serve as a valuable resource for in-depth study of the mechanism of ATO, discovery of new drug combination strategies, promotion of rational drug use and individualized treatments. ATOdb is freely available at http://bio-bigdata.hrbmu.edu.cn/ATOdb/index.jsp.

An overview of arsenic trioxide-involved combined treatment algorithms for leukemia: basic concepts and clinical implications.

Arsenic trioxide is a first-line treatment drug for acute promyelocytic leukemia, which is also effective for other kinds of leukemia. Its side effects, however, limit its clinical application, especially for patients with complex leukemia symptoms. Combination therapy can effectively alleviate these problems. This review summarizes the research progress on the combination of arsenic trioxide with anticancer drugs, vitamin and vitamin analogs, plant products, and other kinds of drugs in the treatment of leukemia. Additionally, the new progress in arsenic trioxide-induced cardiotoxicity was summarized. This review aims to provide new insights for the rational clinical application of arsenic trioxide.

The involvement and therapeutic potential of lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway in arsenic trioxide-induced cardiotoxicity.

BACKGROUND/AIMS: Arsenic trioxide (ATO) is the first-line therapeutic drug for acute promyelocytic leukemia. However, the cardiotoxicity of ATO limits its clinical application. This study aims to explore the long noncoding RNA (lncRNA) involved molecular mechanism in ATO-induced cardiotoxicity and to identify available prevention strategies. METHODS: ATO was administered to mice or primary cultured mouse cardiomyocytes. Small interfering RNA targeting lncRNA Kcnq1ot1 (si-Kcnq1ot1) was used to knockdown lncRNA Kcnq1ot1. MiR-34a-5p mimic and antisense morpholino oligonucleotide targeting miR-34a-5p (AMO-34a-5p) were used to upregulate and downregulate the expression of miR-34a-5p, respectively. TUNEL staining was conducted to detect cell DNA damage. Flow cytometry assay was used to detect cell apoptosis. Western blot was conducted to detect Bcl-2, Bax and Sirt1 protein expression. Real-time PCR was used to detect lncRNA Kcnq1ot1, miR-34a-5p, and Sirt1 mRNA expression. Dual-luciferase reporter assay was performed to validate the predicted binding site. RESULTS: ATO induced apoptosis in cardiomyocytes both in vivo and in vitro. Simultaneously, the expression of lncRNA Kcnq1ot1 and Sirt1 was downregulated, and miR-34a-5p was upregulated. MiR-34a-5p has binding sites with lncRNA Kcnq1ot1 and Sirt1. Knockdown of lncRNA Kcnq1ot1 induced apoptosis of cardiomyocytes, with increased miR-34a-5p and decreased Sirt1 expression. Inhibition of miR-34a-5p attenuated si-Kcnq1ot1-induced apoptosis in cardiomyocytes. Therefore, the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 signaling pathway is involved in ATO-induced cardiotoxicity. Propranolol alleviated ATO-induced apoptosis in cardiomyocytes both in vivo and in vitro, which was related to the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 signaling pathway. CONCLUSION: The lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway is involved in ATO-induced cardiotoxicity. Propranolol can attenuate ATO-induced cardiotoxicity at least partially through the lncRNA Kcnq1ot1/miR-34a-5p/Sirt1 pathway. Combined administration with propranolol may be a new strategy for alleviating the cardiotoxicity of ATO.

Integration of cancer stemness and neoantigen load to predict responsiveness to anti-PD1/PDL1 therapy.

Background: Anti-programmed cell death 1/programmed cell death ligand 1 (PD1/PDL1) therapy is an important part of comprehensive cancer therapy. However, many patients suffer from non-response to therapy. Tumor neoantigen burden (TNB) and cancer stemness play essential roles in the responsiveness to therapy. Therefore, the identification of drug candidates for anti-PD1/PDL1 therapy remains an unmet need. Methods: Three anti-PD1/PDL1 therapy cohorts were obtained from GEO database and published literatures. Cancer immune characteristics were analyzed using CIBERSORTX, GSVA, and ESTIMATE. WGCNA was employed to identify the gene modules correlated with cancer TNB and stemness. A machine-learning method was used to construct the immunotherapy resistance score (TSIRS). Pharmacogenomic analysis was conducted to explore the potential alternative drugs for anti-PD1/PDL1 therapy resistant patients. CCK-8 assay, EdU assay and wound healing assay were used to validate the effect of the predicted drug on cancer cells. Results: The therapy response and non-response cancer groups have different microenvironment features. TSIRS was developed based on tumor neoantigen and stemness. TSIRS can effectively predict the outcomes of patients with anti-PD1/PDL1 therapy in training, validation and meta cohorts. Meanwhile, TSIRS can reflect the characteristics of tumor microenvironment during anti-PD1/PDL1 therapy. PF-4708671 is identified as a potential alternative drug for patients with resistance to anti-PD1/PDL1 therapy. It possesses significant inhibitive effect on the proliferation and migration of BGC-823 cells. Conclusion: TSIRS is an effective tool in the identification of candidate patients who will be benefit from anti-PD1/PDL1 therapy. Small molecule drug PF-4708671 has the potential to be used in anti-PD1/PDL1 therapy resistant patients.

Integrated Analysis Revealing the Senescence-Mediated Immune Heterogeneity of HCC and Construction of a Prognostic Model Based on Senescence-Related Non-Coding RNA Network.

Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Non-coding RNAs play an important role in HCC. This study aims to identify a senescence-related non-coding RNA network-based prognostic model for individualized therapies for HCC. Methods: HCC subtypes with senescence status were identified on the basis of the senescence-related genes. Immune status of the subtypes was analyzed by CIBERSORT and ESTIMATE algorithm. The differentially expressed mRNAs, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) were identified between the two HCC subtypes. A senescence-based competing endogenous RNA (ceRNA) co-expression network in HCC was constructed. On the basis of the ceRNA network, Lasso Cox regression was used to construct the senescence-related prognostic model (S score). The prognosis potential of the S score was evaluated in the training dataset and four external validation datasets. Finally, the potential of the prognostic model in predicting immune features and response to immunotherapy was evaluated. Results: The HCC samples were classified into senescence active and inactivate subtypes. The senescence active group showed an immune suppressive microenvironment compared to the senescence inactive group. A total of 2,902 mRNAs, 19 miRNAs, and 308 lncRNAs were identified between the two subtypes. A ceRNA network was constructed using these differentially expressed genes. On the basis of the ceRNA network, S score was constructed to predict the prognosis of patients with HCC. The S score was correlated with immune features and can predict response to immunotherapy of cancer. Conclusion: The present study analyzed the biological heterogeneity across senescence-related subtypes and constructed a senescence-related ceRNA-network-based prognostic model for predicting prognosis and immunotherapy responsiveness.

The whole transcriptome analysis and the circRNA-lncRNA network construction in arsenic trioxide-treated mice myocardium.

BACKGROUND/AIMS: Arsenic trioxide (ATO) is an effective anti-cancer drug. Nonetheless, it possesses cardiotoxic effects which limit its clinical application. The present study aims to elucidate the molecular basis of ATO-induced cardiotoxicity through using whole transcriptome analysis. METHODS: The whole transcriptome in ATO-treated mice myocardium was analyzed using RNA sequencing technique. These results were confirmed by real-time PCR. The lncRNA-mRNA and circRNA-mRNA co-expression networks were constructed. Finally, a circRNA-lncRNA co-regulated competing endogenous RNA (ceRNA) network was constructed. GO and KEGG pathway analyses were performed. The expression levels of Txnip and Spp1 in ATO-treated neonatal mouse cardiomyocytes were validated by real-time PCR. RESULTS: A total of 113 mRNAs, 159 lncRNAs, 35 miRNAs, and 94 circRNAs were differentially expressed in ATO-treated mice myocardium. A lncRNA-circRNA co-regulation network was constructed. Function annotation revealed that aberrantly expressed genes may be enriched in the 'Wnt signaling pathway', 'Hippo signaling pathway', 'Notch signaling pathway', etc. Finally, the expression levels of Txnip and Spp1 were validated in ATO-treated cardiomyocytes, which was in accordance with the RNA-sequencing results. CONCLUSION: ATO altered coding and noncoding RNA profiles in myocardium of mice. The ATO-related lncRNA-circRNA co-regulation network was constructed. Genes in the co-regulation network are likely to play important roles in the cardiotoxicity of ATO. This study provides new insights into the prevention and treatment of ATO-induced cardiotoxicity.

Comprehensive molecular characterization of hypertension-related genes in cancer.

BACKGROUND: During cancer treatment, patients have a significantly higher risk of developing cardiovascular complications such as hypertension. In this study, we investigated the internal relationships between hypertension and different types of cancer. METHODS: First, we comprehensively characterized the involvement of 10 hypertension-related genes across 33 types of cancer. The somatic copy number alteration (CNA) and single nucleotide variant (SNV) of each gene were identified for each type of cancer. Then, the expression patterns of hypertension-related genes were analyzed across 14 types of cancer. The hypertension-related genes were aberrantly expressed in different types of cancer, and some were associated with the overall survival of patients or the cancer stage. Subsequently, the interactions between hypertension-related genes and clinically actionable genes (CAGs) were identified by analyzing the co-expressions and protein-protein interactions. RESULTS: We found that certain hypertension-related genes were correlated with CAGs. Next, the pathways associated with hypertension-related genes were identified. The positively correlated pathways included epithelial to mesenchymal transition, hormone androgen receptor, and receptor tyrosine kinase, and the negatively correlated pathways included apoptosis, cell cycle, and DNA damage response. Finally, the correlations between hypertension-related genes and drug sensitivity were evaluated for different drugs and different types of cancer. The hypertension-related genes were all positively or negatively correlated with the resistance of cancer to the majority of anti-cancer drugs. These results highlight the importance of hypertension-related genes in cancer. CONCLUSIONS: This study provides an approach to characterize the relationship between hypertension-related genes and cancers in the post-genomic era.

Application of a traction metal clip with a fishhook-like device in wound sutures after endoscopic resection

Background/Aims@#Endoscopic wound suturing is an important factor that affects the ability to remove large and full-thickness lesions during endoscopic resection. We aimed to evaluate the effect of a traction metal clip with a fishhook-like device on wound sutures after endoscopic resection. @*Methods@#From July 2020 to April 2021, patients who met the enrollment criteria were treated with a fishhook-like device during the operation to suture the postoperative wound (group A). Patients with similar conditions and similar size wounds who were treated with a “purse-string suture” to suture the wounds were retrospectively analyzed as the control group (group B). Difference in the suture rate, adverse events, time required for suturing, and number of metal clips were compared between the two groups. @*Results@#The time required for suturing was 7.72±0.51 minutes in group A and 11.50±0.91 minutes in group B. This difference was statistically significant (F=13.071, p=0.001). The number of metal clamps used in group A averaged 8.1 pieces/case, and the number of metal clamps used in group B averaged 7.3 pieces/case. This difference was not statistically significant (F=0.971, p>0.05). @*Conclusions@#The traction metal clip with the fishhook-like device is ingeniously designed and easy to operate. It has a good suture effect on the wound after endoscopic submucosal dissection and effectively prevents postoperative adverse events.

Corrigendum: Downregulation of miR-135b-5p Suppresses Progression of Esophageal Cancer and Contributes to the Effect of Cisplatin.

[This corrects the article DOI: 10.3389/fonc.2021.679348.].

The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

HIV Tat Protein Induces Myocardial Fibrosis Through TGF-ß1-CTGF Signaling Cascade: A Potential Mechanism of HIV Infection-Related Cardiac Manifestations.

Human immunodeficiency virus (HIV) infection is a risk factor of cardiovascular diseases (CVDs). HIV-infected patients exhibit cardiac dysfunction coupled with cardiac fibrosis. However, the reason why HIV could induce cardiac fibrosis remains largely unexplored. HIV-1 trans-activator of transcription (Tat) protein is a regulatory protein, which plays a critical role in the pathogenesis of various HIV-related complications. In the present study, recombinant Tat was administered to mouse myocardium or neonatal mouse cardiac fibroblasts in different doses. Hematoxylin-eosin and Masson's trichrome staining were performed to observe the histological changes of mice myocardial tissues. EdU staining and MTS assay were used to evaluate the proliferation and viability of neonatal mouse cardiac fibroblasts, respectively. Real-time PCR and western blot analysis were used to detect CTGF, TGF-ß1, and collagen I mRNA and protein expression levels, respectively. The results showed that Tat promoted the occurrence of myocardial fibrosis in mice. Also, we found that Tat increased the proliferative ability and the viability of neonatal mouse cardiac fibroblasts. The protein and mRNA expression levels of TGF-ß1 and CTGF were significantly upregulated both in Tat-treated mouse myocardium and neonatal mouse cardiac fibroblasts. However, co-administration of TGF-ß inhibitor abrogated the enhanced expression of collagen I induced by Tat in neonatal mouse cardiac fibroblasts. In conclusion, Tat contributes to HIV-related cardiac fibrosis through enhanced TGF-ß1-CTGF signaling cascade.

Downregulation of miR-135b-5p Suppresses Progression of Esophageal Cancer and Contributes to the Effect of Cisplatin.

Esophageal cancer (EC) is one of the commonest human cancers, which accompany high morbidity. MicroRNAs (miRNAs) play a pivotal role in various cancers, including EC. Our research aimed to reveal the function and mechanism of miR-135b-5p. Our research identified that miR-135b-5p was elevated in EC samples from TCGA database. Correspondingly real-time PCR assay also showed the miR-135b-5p is also higher expressed in Eca109, EC9706, KYSE150 cells than normal esophageal epithelial cells (Het-1A). CCK8, Edu, wound healing, Transwell assay, and western blot demonstrated miR-135b-5p inhibition suppresses proliferation, invasion, migration and promoted the apoptosis in Eca109 and EC9706 cells. Moreover, the miR-135b-5p inhibition also inhibited xenograft lump growth. We then predicted the complementary gene of miR-135b-5p using miRTarBase, TargetScan, and DIANA-microT. TXNIP was estimated as a complementary gene for miR-135b-5p. Luciferase report assay verified the direct binding site for miR-135b-5p and TXNIP. Real-time PCR and western blot assays showed that the inhibition of miR-135b-5p remarkably enhanced the levels of TXNIP in Eca109 and EC9706 cells. Furthermore, cisplatin (cis-diamminedichloroplatinum II, DDP) decreased miR-135b-5p expression and increased TXNIP expression. Enhanced expression of miR-135b-5p attenuated the inhibitory ability of cisplatin (cis-diamminedichloroplatinum II, DDP) in Eca109 cells, accompanied by TXNIP downregulation. In conclusion, the downregulation of miR-135b-5p suppresses the progression of EC through targeting TXNIP. MiR-135b-5p/TXNIP pathway contributes to the anti-tumor effect of DDP. These findings may provide new insight into the treatment of EC.

Comprehensive characterization of a drug-resistance-related ceRNA network across 15 anti-cancer drug categories.

Cancer is still a major health problem around the world. The treatment failure of cancer has largely been attributed to drug resistance. Competitive endogenous RNAs (ceRNAs) are involved in various biological processes and thus influence the drug sensitivity of cancers. However, a comprehensive characterization of drug-sensitivity-related ceRNAs has not yet been performed. In the present study, we constructed 15 ceRNA networks across 15 anti-cancer drug categories, involving 217 long noncoding RNAs (lncRNAs), 158 microRNAs (miRNAs), and 1,389 protein coding genes (PCGs). We found that these ceRNAs were involved in hallmark processes such as "self-sufficiency in growth signals," "insensitivity to antigrowth signals," and so on. We then identified an intersection ceRNA network (ICN) across the 15 anti-cancer drug categories. We further identified interactions between genes in the ICN and clinically actionable genes (CAGs) by analyzing the co-expressions, protein-protein interactions, and transcription factor-target gene interactions. We found that certain genes in the ICN are correlated with CAGs. Finally, we found that genes in the ICN were aberrantly expressed in tumors, and some were associated with patient survival time and cancer stage.

Downregulation of miR-200a protects cardiomyocyte against apoptosis.

BACKGROUND/AIMS: Acute myocardial infarction (AMI) is a major clinical manifestation of ischemic heart disease and represents a significant cause of morbidity and mortality. However, key regulators in the pathogenesis of ischemic heart disease remain controversial. The present study was designed to investigate the involvement of miR-200a and its related mechanism in AMI. METHODS: Left coronary artery (LCA) ligation was conducted to induce an AMI mouse model. The infarct size was measured by TTC staining. H2O2 was used to induce an AMI model in vitro. miR-200a mimics, anti-miR-200a antisense oligodeoxyribonucleotides (AMO-200a), as well as corresponding negative controls were transfected into cardiomyocytes to observe the effect of miR-200a. Flow cytometry was used to detect cell apoptosis. Real-time PCR, immunofluorescence and western blot assays were used to evaluate gene expression at RNA or protein levels, respectively. RESULTS: Apoptosis was activated in AMI models. The expression of miR-200a was upregulated both in the peri-infarcted region of mice myocardium and H2O2-treated cardiomyocytes. The co-administration of AMO-200a decreased the number of apoptosis cells and altered the expression of apoptosis related proteins. Interestingly, bioinformatics analysis results revealed that miR-200a could bind to the 3'-untranslated regions (3'-UTR) of Fus mRNA. In addition, the expression of Fus was downregulated in the AMI mouse models and in H2O2-treated cardiomyocytes. The alteration of miR-200a negatively regulated Fus expression in cardiomyocytes. Also, the protective effect of AMO-200a was observed through its regulation of Fus. CONCLUSION: MiR-200a-dependent apoptosis signaling pathway plays an important role in the pathogenesis of AMI injury and could be an exciting potential therapeutic target.

Effects of diphyllin as a novel V-ATPase inhibitor on TE-1 and ECA-109 cells.

Diphyllin is a natural component of traditional Chinese medicine, which effectively inhibits V-ATPase activity and affects the progression of cancer. However, few studies have been conducted on esophageal cancer, and the mechanisms remain to be elucidated. The present study revealedthat diphyllin inhibited proliferation and induced S arrest in esophageal cancer cell lines TE-1 and ECA-109. Further experiments revealed that diphyllin inhibited V-ATPase activity and decreased the mRNA expression of mammalian target of rapamycin complex 1 (mTORC1), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF). The present study also revealed that diphyllin inhibited proliferation and reduced the formation of new blood vessels. Diphyllin inhibited blood metastasis by regulating the mTORC1/HIF-1α-/VEGF pathway, therefore it could be considered as a new V-ATPase inhibitor to treat esophageal cancer.

Lentivirus-mediated RNAi knockdown of LMP2A inhibits the growth of the Epstein-Barr-associated gastric carcinoma cell line GT38 in vitro.

In this study, lentivirus-mediated RNA interference (RNAi) was applied to inhibit latent membrane protein 2A (LMP2A) gene expression, in order to explore the effects of LMP2A silencing on the growth of an Epstein-Barr virus-associated gastric carcinoma (EBVaGC) cell line in vitro. Lentivirus-mediated RNAi technology was employed to specifically knock down the LMP2A gene in the EBV-positive gastric carcinoma cell line GT38. After infection, reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry and colony formation assays were conducted to evaluate the expression of LMP2A and the biological behavior of the GT38 cell line in vitro. The results showed that the expression of the LMP2A gene was clearly downregulated in the infected cells, which indicated that a highly efficient and stable lentivirus vector was successfully constructed. In the GT38 cells in which the expression of LMP2A was downregulated, the proliferation and colony formation of the cells was significantly inhibited. In addition, it was found that the cell cycle of the GT38 cells was arrested in the G0/G1 phase and the apoptosis rate was increased. These results indicate that lentivirus-mediated RNAi knockdown of LMP2A inhibits the growth of the EBVaGC cell line GT38 in vitro, and suggests that LMP2A is a potential target for gene therapy in the treatment of EBVaGC.

[Association of interleukin-23 receptor gene polymorphisms with susceptibility and phenotypes of inflammatory bowel diseases in Jiangsu Han population].

OBJECTIVE: To investigate the possible association of interleukin-23 receptor (IL-23R) polymorphisms with the susceptibility and phenotype of inflammatory bowel diseases (IBD) in Jiangsu Han population. METHODS: We genotyped 178 IBD patients including 135 patients with ulcerative colitis (UC), 43 patients with Crohn's disease (CD), and 134 healthy controls for rs11805303, rs1343151, rs11465804, rs11209032, rs17375018, rs11465788. RESULTS: Comparing with the controls (50.4%), there was a significant increase in the carriage of the T allele of rs11805303 in UC (60.4%)(P = 0.020). In genotype-phenotype correlation of rs17375018 in UC, clinical severity (UCDAI) was associated with the prevalence of the G allele showed a trend to mild activity. Genotype polymorphisms of rs17375018A was observed more in younger than 25 in the genotype-phenotype correlation in CD (41.7% vs 22.0%, P = 0.050, OR = 2.532, 95%CI 0.988 - 6.494), while rs11805303 was associated with age at diagnose and disease lesion (P = 0.039 and 0.044). The risk of extra intestinal manifestation in rs17375018A allele carriers was lower (23.1% vs 46.7%, P = 0.040, OR = 2.917, 95%CI 1.027 - 8.283). CONCLUSIONS: We confirmed the susceptibility of rs11805303 polymorphisms with UC and first demonstrated the genotype-phenotype correlation of rs11805303, rs17375018 with UC, CD in Jiangsu Han population.

[Toll-like receptor gene polymorphisms and susceptibility to inflammatory bowel disease in Chinese Han and Caucasian populations].

OBJECTIVE: To explore the distribution of Toll-like receptors gene polymorphisms in inflammatory bowel disease (IBD) in Chinese Han patients and Caucasians. METHODS: The toll-like receptor 2 (TLR2) genes Arg677Trp and Arg753Glu, TLR4 genes Asp299Gly and Thr399Ile, and TLR9 gene 1237T/C polymorphisms were genotypes in 113 patients with IBD and 120 age and gender-matched healthy controls by the analyses of polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). A meta-analysis was performed to test whether TLR4 Asp299Gly and Thr399Ile polymorphisms were associated with ulcerative colitis (UC) or Crohn's disease (CD) susceptibility and whether 299Gly carriage was associated with phenotypes of CD patients in the Caucasian population. RESULTS: We found two carriers of TLR9 1237C in UC patients, one carrier in CD patients and one in healthy controls respectively (CD: P = 0.361; UC: P = 0.569). There was no statistically significant difference in both allelic and genotypic frequencies. The mutant genotypes of TLR2 gene Arg677Trp and Arg753Glu, TLR4 gene Asp299Gly and Thr399Ile were not found in either the IBD patients or the healthy controls. The TLR4 299G allele showed a significant association with CD and UC in Caucasian population (OR = 1.29, 95%CI: 1.08 - 1.54, P = 0.004 and OR = 1.28, 95%CI: 1.08 - 1.51, P = 0.004 respectively). Similar association was detected between T399I polymorphism and susceptibility to IBD (OR = 1.37, 95%CI: 1.12 - 1.68, P = 0.002 and OR = 1.46, 95%CI: 1.13 - 1.88, P = 0.003 respectively). However, no significant association was identified between CD phenotypes and 299Gly carriage. CONCLUSION: TLR2 genes Arg677Trp and Arg753Glu, TLR4 genes Asp299Gly and Thr399Ile and TLR9 gene 1237T/C polymorphisms are not associated with IBD in Chinese Han patients. In Caucasians, both TLR4 299G and 399I confer a significant risk for developing CD and UC. The contribution of genetic determinants may differ significantly between ethnicities.

The Toll-like receptor 4 D299G and T399I polymorphisms are associated with Crohn's disease and ulcerative colitis: a meta-analysis.

BACKGROUND: Some studies have reported that Toll-like receptor 4 (TLR4) D299G and T399I polymorphisms are associated with increased Crohn's disease (CD) and ulcerative colitis (UC) risk in the Caucasian population. However, the results have been inconsistent. METHODS: A systemic review of the published data (16 studies with 8,387 cases and 7,013 controls for D299G; 8 studies with 3,881 cases and 1,861 controls for T399I) was undertaken and a meta-analysis was performed to test whether TLR4 D299G and T399I polymorphisms were associated with CD or UC susceptibility and whether 299Gly carriage was associated with phenotypes of CD patients. RESULTS: The TLR4 299Gly allele showed a significant association with CD and UC in the Caucasian population (OR 1.29, 95% CI 1.08-1.54, and OR 1.28, 95% CI 1.08-1.51, respectively). Similar association was detected between the T399I polymorphism and susceptibility to CD and UC (OR 1.37, 95% CI 1.12-1.68, and OR 1.46, 95% CI 1.13-1.88, respectively). However, no significant association was identified between CD phenotypes and 299Gly carriage. CONCLUSION: The meta-analysis showed that TLR4 D299G and T399I confer a significant risk for developing CD and UC in Caucasians. Additional well-powered studies of the association between TLR4 variants and UC are needed.