Zhengting Wang

Polymorphisms of the vitamin D receptor gene and the risk of inflammatory bowel disease: a meta-analysis.

The gene encoding vitamin D receptor (VDR) is recognized as a promising candidate for indicating the development of inflammatory bowel disease (IBD). Four genetic polymorphisms (ApaI, BsmI, FokI, TaqI) in VDR have been widely evaluated to determine their association with IBD, and the results of these evaluations are often inconsistent. Therefore, we conducted a meta-analysis to shed some light on this issue and explored the sources of the heterogeneity between studies. We identified six articles for ApaI (cases/controls: 1902/1468), eight for TaqI (3053/2145), and five each for BsmI (1512/1616) and FokI (2315/1676). Data were analyzed under the random-effects model, and heterogeneity was explored by subgroup analyses. Overall, except for TaqI in allelic comparison [odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.83-0.98], ApaI, BsmI, and FokI polymorphisms showed no significant associations with IBD across different genetic models of inheritance. However, subgroup analyses indicated significance for the association of ApaI with Crohns disease (CD) risk (AA versus aa: OR = 1.40; 95%CI = 1.05-1.88), for BsmI in East Asians (BB plus Bb versus bb: OR = 1.77, 95%CI = 1.14-2.74), for TaqI in Caucasians (TT plus Tt versus tt: OR = 0.79, 95%CI = 0.63- 1.00), and with ulcerative colitis (UC) risk (T versus t: OR = 0.89, 95%CI = 0.80-0.99). There was a low probability of publication bias for all studied polymorphisms. Pooling previous individual studies on IBD, our findings demonstrated that the ApaI polymorphism may increase the risk of CD, whereas the TaqI polymorphism may decrease the risk of UC, especially in Caucasians. Moreover, this study leaves open the question of divergent genetic profiles across different ethnic groups.

Association between CD14 Gene C-260T Polymorphism and Inflammatory Bowel Disease: A Meta-Analysis

Background The gene encoding CD14 has been proposed as an IBD-susceptibility gene with its polymorphism C-260T being widely evaluated, yet with conflicting results. The aim of this study was to investigate the association between this polymorphism and IBD by conducting a meta-analysis. Methodology/Principal Findings Seventeen articles met the inclusion criteria, which included a total of 18 case-control studies, including 1900 ulcerative colitis (UC) cases, 2535 Crohns disease (CD) cases, and 4004 controls. Data were analyzed using STATA software. Overall, association between C-260T polymorphism and increased UC risk was significant in allelic comparison (odds ratio [OR]  = 1.21, 95% confidence interval [CI]: 1.02–1.43; P = 0.027), homozygote model (OR  = 1.44, 95% CI: 1.03–2.01; P = 0.033), as well as dominant model (OR  = 1.36, 95% CI: 1.06–1.75; P = 0.016). However, there was negative association between this polymorphism and CD risk across all genetic models. Subgroup analyses by ethnicity suggested the risk-conferring profiles of -260T allele and -260 TT genotype with UC in Asians, but not in Caucasians. There was a low probability of publication bias. Conclusions/Significance Expanding previous results of individual studies, our findings demonstrated that CD14 gene C-260T polymorphism might be a promising candidate marker in susceptibility to UC, especially in Asians.

MicroRNA-199a-3p is downregulated in gastric carcinomas and modulates cell proliferation.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of targeted mRNAs. An increasing amount of evidence indicates that miRNAs play important role in cancer pathogenesis, apoptosis, proliferation, and differentiation as oncogenes or tumor suppressors. Recently, miRNA-199a has been shown to be involved in many human cancers, although the role of miRNA-199a-3p in gastric cancer has not yet been evaluated. In the present study, the expression of miRNA-199a-3p was found to be significantly downregulated in human gastric cancer tissues and cells. miRNA-199a-3p induced anti-proliferation effects on human gastric cancer cells. Furthermore, using quantitative RT-PCR (real-time polymerase chain reaction) and luciferase reporter assays, mTOR was identified as a direct target gene of miRNA-199a-3p that is downregulated by it. In conclusion, our findings suggest that miRNA-199a-3p is associated with human gastric cancer through its ability to decrease cancer cell proliferation and target the mTOR signaling pathway, and, therefore, may provide a novel therapeutic target for the treatment of human gastric cancer.

mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile

It has been established that mammalian target of Rapamycin (mTOR) inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS)-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD). Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL)-17A, IL-1β,IL-6 and tumor necrosis factor(TNF)-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1) cells and TH17 cells and increases regulatory T (Treg) cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.

RAGE gene three polymorphisms with Crohn's disease susceptibility in Chinese Han population.

AIM To investigate the association of three polymorphisms in the receptor for advanced glycation end product (RAGE) gene with Crohns disease (CD) risk in a Chinese population. METHODS A hospital-based case-control association study involving 312 CD patients and 479 healthy controls was conducted. Peripheral blood samples were collected from 791 study subjects, and genomic DNA was extracted. Genotyping was performed using polymerase chain reaction-ligase detection reaction method. The association between polymorphic genotype and CD predisposition was determined using odds ratio and 95% confidence interval (CI). Data were analyzed using Haplo.stats program. RESULTS Significant differences were observed between patients and controls in allele/genotype distributions of rs1800624 (P(allele)=0.012; P(genotype)=0.005) and in allele distributions of rs2070600 (P=0.02). The risk for CD associated with the rs1800624-A mutant allele decreased by 36% (95%CI: 0.47-0.88, P = 0.005) under the additive model and by 35% (95%CI: 0.46-0.91, P=0.013) under the dominant model. Carriers of rs2070600-A mutant allele showed a 37% (95%CI: 1.02-1.83, P=0.036) increased risk of developing CD relative to the GG genotype carriers. In haplotype analysis, haplotype T-A-G (in the order rs1800625, rs1800624, and rs2070600) decreased the odds of CD by 33% (95%CI: 0.49-0.94, P=0.018). CONCLUSION CD is an immune-related disease with genetic predisposition. Genetic defects in the RAGE gene are strongly associated with CD in Chinese population.

Association between STAT3 gene Polymorphisms and Crohn’s diseasesusceptibility: a case–control study in a Chinese Han population

BackgroundCrohn’s disease (CD) is an immune-related disease with geneticpredisposition. This study aimed to investigate the association of threepolymorphisms in the signal transducer and activator of transcription 3(STAT3) gene with CD risk in a Chinese population.MethodsWe conducted a hospital-based case–control study involving 232 CDpatients and 272 controls. Genotyping was performed using polymerase chainreaction with sequence-specific primer method. Statistical analyses wereconducted using logistic regression and genotype risk scoring.ResultsSignificant differences were found between patients and controls inallele/genotype distributions of rs744166(P allele = 0.0008;P genotype = 0.003) and allele distributions ofrs4796793 (P = 0.03). The risk for CD associated withthe rs744166-A mutant allele decreased by 37% [95% confidence interval (CI):0.48–0.83] under the additive model, 39% (95% CI: 0.43–0.81)under the dominant model and 57% (95% CI: 0.24–0.77) under therecessive model. Carriers of the rs4796793-G mutant allele exhibited 25%(95% CI: 0.58–0.98; P = 0.03) and 47% (95% CI:0.30–0.95) decreased risks of developing CD under the additive andrecessive models, respectively.ConclusionsSTAT3 rs744166 and rs4796793 polymorphisms may be associated with CDoccurrence and used as a predictive factor of CD in Chinese Hanpopulations.Virtual SlidesThe virtual slide(s) for this article can be found here:http://diagnosticpathology.slidepath.com/webViewer.php?snapshotId=1297687014

Meta-analysis of the NAD(P)H: quinine oxidoreductase 1 gene 609 C>T polymorphism with esophageal cancer risk.

Association between the NAD(P)H: quinine oxidoreductase 1 (NQO1) gene 609 C>T polymorphism and esophageal cancer (EC) has been widely evaluated; however, the results are often irreproducible. We thus aimed to comprehensively evaluate this association through a meta-analysis. Data were extracted from 10 study populations involving 1390 EC patients and 1812 controls, and were analyzed using STATA software. Random-effects model was applied irrespective of between-study heterogeneity, which was assessed by the inconsistency index (I(2)) statistic. Publication bias was weighted by the funnel plot and Eggers test. Genotype distributions of the NQO1 gene 609 C>T polymorphism met Hardy-Weinberg equilibrium in controls for all studies. Allelic comparison indicated that NQO1 609 T allele conferred an increased risk (odds ratio [OR]=1.23; 95% confidence interval [CI]: 1.02-1.49; p=0.035), accompanying significant heterogeneity (I(2)=63.4%, p=0.003) and no publication bias (p(Egger)=0.391). This association was potentially enhanced in homozygous comparison (OR=1.58; 95% CI: 1.03-2.41; p=0.035; I(2)= 55.4%, p(heterogeneity)=0.017 and p(Egger)=0.461). Under dominant and recessive models, similar associations were obtained with an increased, although marginally significant risk. Subgroup analysis by ethnicity supported the risk profiles of the NQO1 gene 609 T allele and 609 TT genotype with EC in Eastern Asians, not in Europeans. Meta-regression analysis indicated that association between the NQO1 gene 609 C>T polymorphism and EC risk was significantly decreased with aging in case-patients (R(2)=-0.57; p=0.042). We expand previous studies by showing that the NQO1 gene 609 C>T polymorphism might contribute to EC occurrence, especially in Eastern Asians.

The NAD(P)H: quinine oxidoreductase 1 (NQO1) gene 609 C>T polymorphism is associated with gastric cancer risk: evidence from a case-control study and a meta-analysis.

UNLABELLED The association between the NAD(P)H quinone oxidoreductase 1 (NQO1) gene C609T polymorphism (rs1800566) and gastric cancer has been widely evaluated, but a definitive answer is so far lacking. We first conducted a case-control study to assess this association in a large Han Chinese population, and then performed a meta-analysis to further address this issue. Although our case-control association study indicated no significant difference in the genotype and allele distributions of C609T polymorphism between gastric cancer patients and controls, in the meta analysis involving 4,000 subjects, comparison of alleles 609T and 609C indicated a significantly increased risk (46%) for gastric cancer (95% confidence interval (95%CI) for odds ratio (OR)=1.20- 1.79) in individuals with the T allele. The tendency was similar to the homozygote (OR=1.81, 95%CI: 1.16-2.84), dominant models (OR=1.41, 95%CI: 1.12-1.79), as well as recessive model (OR=1.58, 95%CI: 1.06-2.35). Stratified analysis by study design demonstrated stronger associations in population-based than in hospital-based studies. And ethnicity-based analysis demonstrated a significant association in Asians. We conclude that the NQO1 gene C609T polymorphism increases the risk for gastric cancer, especially in Asian populations.

Lack of association between the interleukin 6 gene -174G>C polymorphism and colorectal cancer: evidence from a meta-analysis.

Interleukin 6 (IL6) is a pleiotropic cytokine involved in physiological processes and in a variety of human malignancies. It is thus a logical candidate for being a causative factor underlying colorectal cancer (CRC). The association between the IL6 -174G>C polymorphism and CRC has been widely evaluated; yet, there is a lack of agreement between studies on the role of this polymorphism in CRC. We performed a meta-analysis to evaluate this association signal. Articles published before May 10, 2012 were included in the meta-analysis. A total of 11 populations incorporating 6481 cases and 7935 controls were included in our analysis. A random-effect model was applied irrespective of between-study heterogeneity. Data and study quality were assessed in duplicate. Overall, the association of the -174G>C polymorphism with CRC was not significant in an allelic comparison model [odds ratio (OR) = 0.99; 95% confidence interval (95%CI) = 0.90-1.09; P = 0.827], a homozygote model (OR = 0.98; 95%CI = 0.83-1.15; P = 0.805), a dominant model (OR = 0.99; 95%CI = 0.87-1.13; P = 0.906), or a recessive model (OR = 0.97; 95%CI = 0.88-1.08; P = 0.610). Furthermore, the analyses of subgroups created based on common study design, genotyping methods, and ethnicity failed to find a significant association of this polymorphism with CRC. Therefore, our results collectively suggest that the IL6 -174G>C polymorphism might not be a potential candidate for CRC risk.

Association between STAT3 gene polymorphisms and ulcerative colitis susceptibility: a case-control study in the Chinese Han population.

Ulcerative colitis (UC) is a chronic inflammation of the large intestine. The aim of this study was to investigate the association of two polymorphisms in STAT3 with the risk of UC development in the Chinese Han population. This is a hospital-based case-control study involving 56 UC patients and 274 controls. Genotyping was performed using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. Statistical analyses were conducted using logistic regression and genotype risk score. Overall, there was a significant difference between patients and controls in the genotype distribution of rs2293152 (P = 0.044). The risk for UC associated with the rs2293152-G mutant allele was increased (odds ratio = 2.76; 95% confidence interval = 1.06- 7.24) under the dominant model. However, we failed to find any obvious differences in the rs4796793 genotype or allele distributions between the UC patients and controls, and did not detect any significant association of the rs4796793 polymorphism with UC across different genetic models of inheritance. Our study implies that the STAT3 rs2293152 polymorphism may be associated with the occurrence of UC and might be used as a predictive factor for UC in the Chinese Han population.