A meta-analysis of the relation of polymorphism at sites −1082 and −592 of the IL-10 gene promoter with susceptibility and clearance to persistent hepatitis B virus infection in the Chinese population

Background

Up to now, many publications about the Chinese population have evaluated the correlation between interleukin-10 (IL-10) ?1082 and ?592 polymorphisms and persistent hepatitis B virus (HBV) infection. However, the results remain inconclusive. In order to resolve this conflict, a meta-analysis was performed.

Methods

Seven studies were included and dichotomous data are presented as the odds ratio (OR) with a 95% confidence interval (CI).

Results

The results of our study suggest that carriers of the IL-10 ?592A allele were more likely to clear HBV spontaneously in the Chinese pooled population (A vs. C: OR = 0.799, 95% CI = 0.678–0.941, P = 0.007; AC vs. AA: OR = 1.343, 95% CI = 1.017–1.684, P = 0.011; AA vs. AC + CC: OR = 0.736, 95% CI = 0.594–0.912; AA + AC vs. CC: OR = 0.588, 95% CI = 0.408–0.848, P = 0.004) and the IL-10 ?1082A allele was associated with significantly reduced persistent HBV infection risk in Chinese (A vs. G: OR = 0.701, 95% CI = 0.494–0.996, P = 0.047; AA vs. GG + GA: OR = 0.684, 95% CI = 0.476–0.982, P = 0.040).

Conclusions

Persistent HBV infection susceptibility is associated with the gene polymorphism IL-10 ?1082GA in the Chinese population and the clearance of HBV is associated with the gene polymorphism IL-10 ?592CA in the Chinese population.     

Hypermethylation of TGF-β1 gene promoter in gastric cancer

AIM:To examine transforming growth factor-β1(TGF-β1)promoter methylation in gastric cancer and to determine if Helicobacter pylori(H.pylori)or interleukin(IL)-1β could induce TGF-β1 hypermethylation in vitro.METHODS:We examined the frequency and extent of TGF-β1 promoter methylation using methylationspecific PCR in the gastric tissues from 47 gastric cancer patients and 39 non-gastric cancer subjects.H.pylori infection was confirmed by a positive result from either a serological test,histological analysis or C13urea breath test.GES-1 and MKN-45 cells co-cultured with H.pylori or treated with IL-1β for 12,24 and 48 h in vitro tested the effects of H.pylori or IL-1β on TGF-1β.RESULTS:Twenty-four/forty-seven(51%)cases of gastric cancer(GC)tissues showed TGF-β1 promoter methylation,15/47(31.9%)cases of matched noncancerous gastric mucosa tissues from the GC patients,and 11/39(28%)case of the normal gastric mucosa tissues from non-GC subjects showed TGF-β1 promoter methylation(51%vs 28%,P<0.05).Significantly higher levels of methylation of TGF-β1 were found in the tumor tissues than in non-tumor tissues from GC patients(0.24±0.06 vs 0.17±0.04,P<0.05)and normal gastric tissues from non-GC subjects(0.24±0.06 vs 0.15±0.03,P<0.05).TGF-β1 methylation was found in 48.3% of H.pylori-positive gastric mucosal tissues whereas only 23.1% of H.pylori-negative gastric mucosal tissues showed TGF-β1 methylation(48.3%vs 23.1%,P<0.05).IL-1β appeared to induce a dose-dependent methylation of TGF-β1 and the strongest methylation was observed in GES-1 cells treated with 2.5 ng/mL of IL-1β for 48 h.Further studies showed that pre-treatment of GES-1 cells with 20ng/mL IL-1RA for 1 h could partially abolish the effect of IL-1β on TGF-β1 methylation.Infection of GES-1cells by H.pylori was not found to induce significant TGF-β1 promoter methylation.CONCLUSION:Our data revealed that TGF-1 promoter is methylated in GC patients.IL-1β may be an important mediator for H.pylori induced gene methylation during GC     

Association of TNF-α and Fas gene promoter polymorphism with the risk of Kashin–Beck disease in Northwest Chinese population

The objective of this study is to investigate the relationship between single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor-α (TNF-α) and Fas genes and Kashin-Beck disease (KBD) in Shaanxi province, Northwest in China. Blood samples of 388 residents were collected from 14 KBD villages in Linyou and Yongshou counties, Shaanxi, Northern of China. One hundred eighty-six cases with KBD and 202 cases of health in KBD areas were diagnosed by "Diagnosis Criterion of Kashin-Beck disease in China (WS/T207- 2010)". The TNF-α -308G/A, TNF-α -238G/A, and Fas -670A/G SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism in combination with sequence analysis in KBD and healthy control groups. The genotypes and allele frequencies distribution of these SNPs were then analyzed. TNF-α -308A allele frequency in KBD patients were significantly higher than that in healthy controls. Although TNF-α -238 genotypes and allele frequencies were not significantly different between KBD patients and the healthy controls, GA genotype and A allele frequency in KBD patients were higher than those in healthy controls. The TNF-α -308G/A SNPs were associated with the susceptibility of KBD.     

Apolipoprotein E polymorphism: Another player in the genetics of colon cancer susceptibility?

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Association of the interleukin-1 β genetic polymorphism and gastric cancer risk in Japanese

Background. Helicobacter pylori infection is associated not only with gastroduodenal ulcers but with the development of gastric cancer. Interleukin-1 β (IL-1 β) is a potent inhibitor of gastric secretion. The −31 C-to-T base transition in the intron of this gene has been reported to be involved in carcinogenic changes within the stomach, especially in H. pylori-infected individuals. Methods. In this study, the −511 T-to-C polymorphism in the IL-1 β gene was investigated in 669 patients with gastric diseases. Results. The allelic frequencies of the C allele, which indicates low acid secretion and is a component of a supposedly high-risk genotype for gastric cancer, were 0.48 in H. pylori-negative noncancer controls, 0.52 in H. pylori-positive noncancer controls, 0.57 in subjects with chronic active gastritis (CAG) with H. pylori, 0.58 in subjects with intestinal metaplasia (IM) or CAG without H. pylori, and 0.52 in gastric cancer patients. Significant differences among the groups were observed between the IM or CAG without H. pylori group and the gastric cancer group and between the IM or CAG without H. pylori group and the H. pylori-negative noncancer control group (P < 0.05). Conclusions. The IL-1 β−511 genetic polymorphism was not associated with gastric cancer in a multistep carcinogenesis model. However, in view of the results for the IM or CAG without H. pylori group, the presence of the C allele may also indicate a risk of mucosal atrophy of the stomach in the Japanese population. Received: February 20, 2001 / Accepted: July 6, 2001     

T-889C IL-1α promoter polymorphism influences the response to oral cyclophosphamide in scleroderma patients with alveolitis

Cyclophosphamide (CYC) is the cornerstone of the treatment of systemic sclerosis (SSc)-associated fibrosing alveolitis (FAS). Despite treatment with CYC, in a not negligible proportion of SSc-FAS patients, deterioration in lung function can be observed. Interleukin-1 (IL-1) cluster gene single nucleotide polymorphisms (SNPs) were implicated in the pathogenesis of some interstitial lung diseases and may favor the progression of restrictive lung disease in SSc. The present retrospective case-control study was conducted on 18 SSc patients previously treated with oral CYC (2 mg/kg) and medium-dose steroids (prednisone 25 mg for 3 months and then tapered to 5 mg/day) for the presence of FAS—defined as the presence of areas of ground-glass attenuation on high-resolution computed tomography (HRCT) and a recent deterioration in lung function. The T/C substitution at position −889 of the IL-1α promoter gene (T-889C) was determined by polymerase chain reaction and restriction length fragment analysis. Patients carrying the T allele showed a significant decrease in forced vital capacity (FVC) values after 12 months of therapy (2.46±1.09 vs 2.59±1.17 l), while wild-type patients showed an increase in FVC values (2.73±0.54 vs 2.54±0.5 l) (p=0.005 between the two groups, analysis of variance for repeated measures). Patients with the T-889C polymorphism presented higher baseline erythrocyte sedimentation rates (ESR) compared to wild-type patients (50.3±25.4 vs 23.3±17.7 mm/h). Baseline ESR inversely correlated with the variation of FVC (ΔFVC) after 12 months of therapy (r=−0.50 and p<0.05). The two groups were otherwise similar with respect to autoantibodies, age, disease duration, disease subset, radiological HRCT grade, and baseline lung physiology. The T-889C polymorphism represents a marker for worse functional responses to CYC in SSc-FAS. The mechanisms by which this SNP may negatively influence the response to CYC therapy are unknown, but might be linked to increased inflammatory responses in the lungs.     

DNA methyltransferase 3B promoter polymorphism and its susceptibility to primary hepatocellular carcinoma in the Chinese Han nationality population： A case-control study

AIM： To investigate the correlation between C/T single nucleotide polymorphism （SNP） in the promoter of the DNA methyltransferase 3B （D/VMT3B） gene and risk for development and progression of primary hepatocellular carcinoma （HCC）. METHODS： One hundred case subjects were selected consecutively from Tongji Hospital （Wuhan, China）. from March to November 2006. They did not receive radiotherapy or chemotherapy for newly diagnosed and histopathologically confirmed HCC. One hundred and forty control subjects having no history of cancerous or genetic diseases were healthy volunteers to Wuhan Blood Center in the same period. Frequency was matched for sex, age, alcohol consumption and cigarette smoking status of the case subjects. C/T polymorphism of the DNMT3B promoter was analyzed using polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） and sequencing analysis. The association between genotypes of DNMT3B and clinicopathological parameters among cases was also studied. RESULTS： The CC genotype HCC patients and controls. was not detected in both In control subjects, the frequency of TT and CT genotypes was 99.3% and 0.7% respectively, and that of T and C alleles was 99.6% and 0.4% respectively. The frequency of CT genotype was higher in HCC （3.0%）. The frequency of T and C alleles was 98.5% and 1.5% respectively. However, the genotype and allelotype distribution in HCC patients was not significantly different from that in controls. CONCLUSION： C/T polymorphism is not associated with the increased risk of HCC. DNMT3B genetic polymorphism is variable in different races, ethnic groups or geographic areas. Further study is needed to clarify the role of DNMT3B SNP in the development of HCCamong other populations.     

DNMT3B 579 G〉T promoter polymorphism and risk of esophagus carcinoma in Chinese

AIM：To investigate the relationship between 579 G〉T polymorphisms in the DNMT3B gene, which is involved in de novo methylation and associated with the risk of esophagus cancer （EC） in Chinese. METHODS：DNMT3B 579 G〉T genotypes were determined by PCR-RFLP in 194 EC patients and 210 healthy controls matched for age and sex, who did not receive radiotherapy or chemotherapy for newly diagnosed and histopathologically confirmed EC. RESULTS：In control subjects, the frequency of T/T and G/T genotypes, and T and G alleles was 81.4%, 18.1%, 90.05% and 9.55%, respectively. The distribution of genotypes and allelotypes in the EC patients was not significantly different from that in the controls. When stratified by sex and age, there was still no significant association between the risks of EC and GT and GG genotypes. This study also showed a distinct difference in the distribution of DNMT3B and single nucleotide polymorphism （SNP） between Chinese and Koreans.CONCLUSION：DNMT3B 579 G〉T polymorphism may not be a stratification marker to predict the susceptibility to EC, at least in Chinese. DNMT3B promoter SNP is diverse in ethnic populations.     

Novel interleukin 1β polymorphism increased the risk of gastric cancer in a Korean population

Background Polymorphisms in the gene for interleukin 1 (IL-1B) have been found to increase the risks of gastric cancer and its precursors in response to Helicobacter pylori infection in white populations. However, there has been no independent confirmation of the role of IL-1B markers in gastric cancer patients from Asian populations. Moreover, there have been conflicting data regarding the effect of IL-1B-511/-31 on the risk of gastric cancer or its precursors in Asian populations. Therefore, we assessed an additional polymorphism in the promoter region of IL-1B at position-1473 with the IL-1B-511/-31 polymorphisms in a Korean population.Methods In a case-control study, including 331 gastric cancer cases and 433 controls, we assessed the association between the three polymorphisms and the risk of gastric cancer. All genotyping was performed in duplicate. To assess the DNA-binding activity of IL-1B-1473 in vitro, we performed an electrophoretic mobility shift assay (EMSA).Results When cases were divided according to the histologic type of the tumor, a significant difference in genotype frequencies for IL-1B-1473 was observed only between intestinal-type cases and controls (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.0–3.5 and OR 2.1 and 95% CI, 1.1–4.2 in the CG and GG genotypes, respectively). In the cases, there was a deviation from Hardy-Weinberg equilibrium in the IL-1B-511/-31 loci confined to the intestinal type, due to the excess of heterozygotes. The IL-1B-1473G allele showed decreased binding to nuclear extract, indicating a wearker promoter activity on EMSA.Conclusions We identified a novel single-nucleotide polymorphism, 1473CG, in the IL-1B promoter that was significantly associated with gastric cancer among Koreans. Our results also suggest that the association between IL-1B polymorphism and an increased risk of gastric cancer may depend on the histologic type of gastric cancer.     

Association of -238G／A polymorphism of tumor necrosis factor-alpha gene promoter region with outcomes of hepatitis B virus infection in Chinese Han population

AIM: To clarify whether -238G/A polymorphism of tumor necrosis factor-a (TNF-a) gene promoter region was associated with outcomes of hepatitis B virus (HBV) infection in Han population of northern China, and to analyze the geneenvironment interaction between -238G/A polymorphism and cigarette smoking or alcohol consumption. METHODS: A case-control study was conducted to analyze the association of TNF-a gene promoter polymorphism with HBV infection outcomes. A total of 207 patients with chronic hepatitis B (HB) and 148 cases of self-limited HBV infection from Ditan Hospital and Shunyi District Hospital in Beijing, respectively were recruited. History of smoking and alcohol drinking was inquired by a questionnaire. The -238G/A polymorphism of TNF-a gene promoter was genotyped by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). RESULTS: The frequencies of GG and GA genotypes were 98.07% and 1.93% in chronic HB patients and 93.24% and 6.76% in self-limited HBV infection individuals, respectively (X^2=5.30, P=-0.02). The frequency of G allele was significantly higher in patients with chronic HB that in individuals with self-limited HBV infection (99.03% vs 96.62%, X^2=5.20, P=0.02). Only modestly increased risk of onset of chronic HB was found in smokers (OR=1.40, 95% CI： 0.87-2.28, P=0.14) and drinkers (OR=-1.26, 95%CI： 0.78-2.05, P=-0.32). There was a positive interaction between genotype GG and cigarette smoking with an interaction index (Ⅱ) of 2.95, or alcohol consumption with an Ⅱ of 1.64. CONCLUSION: The -238G/A polymorphism of TNF-a gene promoter region is independently associated with different outcomes of HBV infection.     

Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma

AIM:To investigate the rrelationship between methylationof Syk(spleen tyrosine kinase)gene in promoter regionand oncogenesis,metastasis of gastric carcinoma.Therelation between silencing of the Syk gene and methylationof Syk promoter region was also studied.METHODS:By using methylation-specific PCR(MSP)technique,the methylation of Syk promoter region inspecimens from 61 gastric cancer patients(tumor tissuesand adjacent normal tissues)was detected.Meanwhile,RT-PCR was used to analyse syk expression exclusively.RESULTS:The expression of the Syk gene was detectedin all normal gastric tissues.Syk expression in gastriccarcinoma was lower in 14 out of 61 gastric cancer samplesthan in adjacent normal tissues(X~2=72.3,P<0.05).Nomethylation of Syk promoter was found in adjacent normaltissues,hypermethylation of Syk gene in promoter wasdetected 21 cases in 61 gastric carcinoma patients.Therate of methylation of Syk promoter in gastric carcinomawas higher than that in adjacent normal tissues(X~2=25.1,P<0.05).In 31 patients with lymph node metastasis,17 werefound with Syk promoter methylation.A significant differencewas noted between two groups(X~2=11.4,P<0.05).CONCLUSION:Hypermethylation leads to silencing of theSyk gene in human gastric carcinoma.Methylation of Sykpromoter is correlated to oncogenesis and metastasis ofgastric carcinoma.Syk is considered to be a potential tumorsuppressor and anti-metastasis gene in human gastric cancer.     

Effect of common polymorphisms in the HNF4α promoter on susceptibility to type 2 diabetes in the French Caucasian population

Aims/hypothesis The gene encoding HNF-4, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4 P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population.Methods Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4 region had been shown.Results The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4 was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage.Conclusions/interpretation None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4 and type 2 diabetes in several ethnic groups.     

Effects of dietary intake and genetic factors on hypermethyiation of the hMLH1 gene promoter in gastric cancer

AIM: Hypermethylation of the promoter of the hMLH1 gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer. METHODS: Data were obtained from a hospital-based, case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age- and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors. Hypermethylation of the hMLH1 gene promoter, polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated. RESULTS: Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene. Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation, whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region, Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53 gene. CONCLUSION: These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and polymorphisms of GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes are not independent risk factors for gastric cancer with hypermethylation of the hMLH1 promoter. These data also suggest that there could be two or more different molecular pathways in the development of gastric cancer, perhaps involving tumor suppression mechanisms or DNA mismatch repair.     

Significance of expression of heat shock protein90α in human gastric cancer

AIM: To evaluate the significance of hsp90α expression in human gastric cancer tissues. METHODS: Immunohistochemical staining was used in clinical specimens from 33 cases of gastric cancer and 33 cases of gastritis with rabbit anti-human hsp90α multi-clonal antibody in order to explore the relationship between the expression of hsp90α in gastric carcinoma tissue and gastritis tissue as well as in mucous membrane adjacent to cancer and lymph node metastasis.RESULTS: Hsp90α was detected in 88% of gastric carcinoma cases and 55 % of gastritis cases. The hsp90α positive rate in gastric cancer group was significantly higher than that in gastritis group (P&lt;0.01, P=0.005). The hsp90α positive rate in gastric cancer and in mucous membrane adjacent to cancer was 88% and 55 % respectively (P&lt;0.01,P=0.005). The hsp90α positive rate in lymph node metastasis group and non-lymph node metastasis group was 100% and 60% respectively, and a significant correlation between hsp90α expression and lymph node metastasis was shown (P&lt;0.01,P=0.005). CONCLUSION: The hsp90α expression rate in gastric cancer group was significantly higher than that in gastritis group as well as that in the group of mucous membrane adjacent tocancer. The hsp90α expression in lymphatic node metastasis group was higher than that in non-lymphatic node metastasisgroup. The results indicate that increased hsp90α expression has a close relationship with occurrence and lymph node metastasis of gastric cancer.     

Chinese diet in the causation and prevention of cancer

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