Xiaolian Zhang

Role of IL-4 gene polymorphisms in HBV-related hepatocellular carcinoma in a Chinese population.

Background Interleukin-4 (IL-4) is best known as an important mediator and modulator of immune and inflammatory responses. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer, and genetic variations in the IL-4 gene may be associated with the risk of hepatitis B virus (HBV)-related HCC. However, few studies have been conducted on their association. Objectives To clarify the effects of IL-4 gene polymorphisms on the risk of HBV-related HCC, two common variants, −590C/T (rs2243250) and −33C/T (rs2070874), and their relationship with HBV-related disease risk were investigated in a Chinese population. Methods IL-4 −590C/T and −33C/T polymorphisms were examined in 154 patients with HBV-related HCC, 62 patients with HBV-induced liver cirrhosis (LC), 129 patients with chronic hepatitis B (CHB), and 94 healthy controls, using the polymerase chain reaction-restriction fragment length polymorphism method and DNA sequencing. Results Overall, no significant differences were observed regarding the IL-4 −590C/T and −33C/T polymorphism genotypes, alleles, or haplotypes between the patient groups and the healthy controls. However, the CC genotypes of IL-4 −590C/T and −33C/T polymorphisms were observed to be significantly associated with CHB in subgroup analysis in males [CC versus TT (OR: 4.193, 95% CI: 1.094–16.071, P = 0.037; and OR: 3.438, 95% CI: 1.032–11.458, P = 0.044) and CC versus TT+CT (OR: 4.09, 95% CI: 1.08–15.49, P = 0.038; and OR: 3.43, 95% CI: 1.04–11.28, P = 0.042)]. Conclusions These findings suggest that genetic variants in IL-4 −590C/T and −33C/T polymorphisms may be a risk factor for CHB in Chinese males but not for HBV-related LC or HCC.

Meta-analysis of the relationship between 14bp insertion/deletion polymorphism of HLA-G gene and susceptibility to systemic lupus erythematosus

We performed a meta-analysis to examine the relationship between the human leukocyte antigen-G (HLA-G) 14 base pairs sequence (14bp) insertion (ins)/deletion (del) polymorphism to systemic lupus erythematosus (SLE). Eligible studies were extracted in PubMed, Embase, Cochrane Library and CNKI (Chinese) up to March 31, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the strength of the association. Finally, 7 studies with 1864 cases and 2259 controls were involved in this meta-analysis. Overall, the HLA-G 14bp ins/del polymorphism was significantly associated with SLE susceptibility (ins vs. del: OR=1.179, 95%CI=1.037-1.341, P=0.012; ins/ins vs. del/del: OR=1.394, 95%CI=1.153-1.684, P=0.001; ins/del vs. del/del: OR=1.199, 95%CI=1.041-1.382, P=0.012; ins/ins+ins/del vs. del/del: OR=1.252, 95%CI=1.097-1.430, P=0.001). When stratified by ethnicity, significance was found in Asians (ins/ins vs. del/del: OR=1.326, 95%CI=1.001-1.756, P=0.049) and Caucasians (ins/ins vs. del/del: OR=1.454, 95%CI=1.126-1.878, P=0.004; ins/del vs. del/del: OR=1.288, 95%CI=1.051-1.579, P=0.015; ins/ins+ins/del vs. del/del: OR=1.340, 95%CI=1.106-1.623, P=0.003). Our results suggest that the HLA-G 14bp insertion allele might act as an increased risk against SLE. Besides, this is the first meta-analysis to report an association between the HLA-G 14bp ins/del polymorphism and SLE. Larger and well-designed studies are needed to further confirm these findings.

Quantitative assessment of CYP2D6 polymorphisms and risk of Alzheimer's disease: a meta-analysis.

BACKGROUND CYP2D6 gene encoding CYP2D6 enzyme belonging to the cytochrome P450 system has aroused long attention being a candidate gene for Alzheimers disease (AD), but the results remain inconsistent and underpowered. OBJECTIVES To investigate the contradictory results, the effect of single CYP2D6 polymorphism- CYP2D6*4, together with CYP2D6 phenotypes on the risk of AD, was evaluated using a meta-analysis. METHODS Electronic database search of PubMed, Embase and Cochrane Library was conducted up to Apr 17, 2014. Odds ratio (OR) along with the 95% confidence interval (CI) was calculated. Subgroup analysis was performed to examine the impact of CYP2D6 variants on different ethnic. Meta-regression was performed to explore possible source of heterogeneity. RESULTS A total of 11 studies involving 643AD cases and 1375 controls were included for CYP2D6*4 polymorphism, and 4 studies consisted of 411AD cases and 603 controls were included for CYP2D6 phenotypes. With respect to CYP2D6*4 polymorphism, significantly increased risk of AD was found in allelic contrast model of A vs. G (OR=1.29, 95%CI=1.03-1.62, P=0.026), co-dominant genetic model AA vs. GG (OR=1.91, 95%CI=1.04-3.51, P=0.038); and recessive genetic model AA vs. AG+GG (OR=1.88, 95%CI=1.03-3.46, P=0.041) in the overall populations. Similar results were also indicated in subgroup analysis in Caucasians. As for CYP2D6 phenotypes, no significant association with AD was revealed. CONCLUSIONS Our data support that the CYP2D6*4 polymorphism but not CYP2D6 phenotypes might be associated with increased AD risk, particularly in Caucasian populations.

An updated meta-analysis between the association of XRCC1 Arg399Gln polymorphism and hepatocellular carcinoma risk

BACKGROUND Various studies have evaluated the relationship between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism and hepatocellular carcinoma (HCC) risk, but the conclusions have been inconsistent and underpowered. The purpose of this updated meta-analysis was to examine whether XRCC1 Arg399Gln polymorphism confers susceptibility to HCC. METHODS Eligible studies extracted from PubMed, Embase, Cochrane Library, VIP (chinese) and CNKI (chinese) up to November 2013 were included in the study. Pooled odds ratio (OR) together with their 95% confidence interval (CI) were estimated to evaluate XRCC1 Arg399Gln polymorphism and HCC risk. RESULTS Finally, 21 studies with 4,170 cases and 5,030 controls were involved in our meta-analysis. The results demonstrated that there was significant association between Arg399Gln polymorphism and HCC risk under two contrast models in overall populations (AG vs GG: OR=1.265, 95%CI=1.036-1.545, p=0.021; AA+AG vs GG: OR=1.240, 95%CI=1.021-1.506, p=0.030). In subgroup analyses, significant association was found in Asians (A vs G: OR=1.175, 95%CI=1.013-1.362, p=0.033; AG vs GG: OR=1.317, 95%CI=1.070-1.622, p=0.009; AA+AG vs GG: OR=1.289, 95%CI=1.055-1.575, p=0.013) and Caucasians (A vs G: OR=0.591, 95%CI=0.361-0.966, p=0.036; AA+AG vs GG: OR=0.468, 95%CI=0.234-0.934, p=0.031). CONCLUSIONS The results suggest that XRCC1 Arg399Gln polymorphism may increase HCC risk especially among Asians. However, XRCC1 Arg399Gln polymorphism might act as a protective role against HCC among Caucasians.

Type conversion of secretomes in a 3D TAM2 and HCC cell co-culture system and functional importance of CXCL2 in HCC

Macrophages play important roles in the tumor microenvironment, driving cancer progression and metastasis, particularly in hepatocellular carcinoma (HCC). However, few studies have assessed the exact secretome composition in HCC. In the present study, the impact of different phenotype of macrophages on HCC cells was investigated. Alternatively activated macrophages (M2) were found to significantly increase the proliferation, migration, and invasion abilities of SMMC7721 cells (all P < 0.05). M2 were then co-cultured with SMMC7721 cells to reconstruct the tumor microenvironment. Conditioned medium from 3D single cultures of M2, SMMC7721 cells, and their co-culture system were analyzed using quantitative proteomics via iTRAQ labeling combined with mass spectrometric analysis. Secretome analysis revealed a total of 159 differential secreted proteins in the co-culture system compared to the single culture systems, with 63 being up-regulated (>1.3-fold) and 96 down-regulated (<0.7-fold). CXCL2 was confirmed to have higher expression in the co-culture system and HCC tissues, and was selected for further investigation. Functional effects data suggested that recombinant human CXCL2 significantly enhanced the migration, invasion ability of SMMC7721 cells, and weakened adhesion ability. While CXCL2 neutralization and CXCR2 blockage significantly inhibited the effects of CXCL2 on SMMC7721 cells, indicating that CXCL2 may play pivotal role in HCC metastasis.

Association between hypoxia-inducible factor-1α gene polymorphisms and risk of chronic hepatitis B and hepatitis B virus-related liver cirrhosis in a Chinese population: a retrospective case-control study.

BACKGROUND Our recent study demonstrated a significant association between HIF-1α polymorphisms and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Since chronic hepatitis B (CHB), liver cirrhosis (LC), and HCC are progressive stages of chronic HBV infection, the aim of this study is to further determine if HIF-1α polymorphisms are associated with CHB and HBV-related LC. METHODS Two HIF-1α polymorphisms (rs11549465 and rs115494657) were examined in 173 healthy controls, 153 patients with CHB, and 132 patients with HBV-related LC, using the polymerase chain reaction-restriction fragment length polymorphism method. DNA sequencing was also used to validate the genotype results. RESULTS There were no significant differences regarding the HIF-1α rs11549465 and rs115494657 polymorphisms between the patient groups and the healthy controls, no matter the genotypes, alleles, or haplotypes. To exclude the potential influence of HBV infection in the association between HIF-1a and HBV-related LC, a comparison between the LC patients and HBV infected patients was also conducted, but a similar insignificant result was found. CONCLUSIONS Our data suggest that the HIF-1α gene polymorphisms might not contribute to the development of CHB and HBV-related LC in a Chinese population.

Lack of association between CYP1A1 polymorphisms and risk of bladder cancer: a meta-analysis.

BACKGROUND The effects of CYP1A1 gene polymorphisms on the risk of bladder cancer (BC) remain controversial. We carried out a meta-analysis to clarify the role of CYP1A1 gene polymorphisms in BC. MATERIAL AND METHODS A comprehensive literature search was conducted up to November 20, 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. Meta-regression, subgroup analysis, sensitivity analysis and publication bias were also performed. RESULTS Eight studies involving 1,059 BC cases and 1,061 controls were included. The meta-analysis showed that there was no significant association between the two common mutations of CYP1A1 and BC risk. For the I1e462Val A/G polymorphism with GG vs. AA the OR was 1.47 (95 % CI= 0.70-3.07, P =0.308). For the MspI T/C polymorphism, though a slight trend was found this was not statistically nonsignificant (CC vs.TT, OR = 1.24, 95 % CI= 0.98-1.58, P =0.078). Subgroup analyses by ethnicity also found no obvious association between CYP1A1 and BC risk. CONCLUSION The present meta-analysis suggests that CYP1A1 polymorphism is not associated with bladder cancer risk.

Association of Ghrelin Gene Polymorphisms and Serum Ghrelin Levels with the Risk of Hepatitis B Virus-Related Liver Diseases in a Chinese Population.

Background The functions of ghrelin (GHRL) include anti-inflammatory effects, reduction of the fibrogenic response, protection of liver tissue, and regulation of cell proliferation. Genetic variations in the GHRL gene may play an important role in the development of chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Therefore, we investigated whether GHRL gene polymorphisms and its serum levels are associated with hepatitis B virus (HBV)-related diseases risk in a Chinese population. Methods 176 patients with CHB, 106 patients with HBV-related LC, 151 patients with HBV-related HCC, and 167 healthy controls were recruited in the study. Genotyping of GHRL rs26311, rs27647, rs696217, and rs34911341 polymorphisms were determined with the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing. The serum GHRL concentrations were determined using enzyme-linked immunosorbent assay (ELISA). Results Binary logistic regression analyses adjusting for gender and age revealed that a significant increased risk of LC was found in the GHRL rs26311 GC genotype and combined GC+CC genotypes when compared with the GG genotype (GC vs. GG: OR = 1.671, 95% CI = 1.013–2.757, P = 0.044; GC+CC vs. GG: OR = 1.674, 95% CI = 1.040–2.696, P = 0.034). In subgroup analysis by gender, binary logistic regression analyses adjusting for age showed that the GHRL rs26311 C allele and combined GC+CC genotypes were associated with a significantly increased risk to LC in males (C vs. G OR = 1.416, 95% CI = 1.017–1.972, P = 0.040; GC+CC vs. GG: OR = 1.729, 95% CI = 1.019–2.933, P = 0.042). In addition, we found significant decreased serum GHRL levels in LC patients compared with the healthy controls. However, there was no significant association of the GHRL rs26311 polymorphism with serum GHRL levels in LC patients. Conclusions These observations suggest that the GHRL rs26311 polymorphism is associated with an increased risk to HBV-related LC, especially in men. We also found an inverse association of serum GHRL levels with LC.

Association of Paraoxonase 1 Gene Polymorphisms With the Risk of Hepatitis B Virus-related Liver Diseases in a Guangxi Population: A Case-control Study.

AbstractParaoxonase 1 (PON1), a liver-induced glycoprotein enzyme responsible for antioxidant defense against reactive oxygen species and anti-inflammatory, has been linked to various cancers. The objective of this study was to explore the association of PON1 rs662 and rs705382 with the risk of chronic hepatitis B (CHB), hepatitis B virus-related liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in patients living in the Guangxi region of southern China.The PON1 rs662 and rs705382 single-nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) in 99 CHB patients, 84 LC patients, 258 HCC patients, and 221 healthy controls.Significant associations with CHB risk were observed for the rs705382 SNP after adjusting for sex, age, ethnicity, smoking, alcohol consumption, and body mass index. When stratified by sex and age, this positive association was significantly strengthened among men and individuals over 40 years old. Moreover, a decreased risk of LC was associated with the rs705382 CG and the combined GG + CG genotypes among women, with borderline statistical significance. In haplotype analyses, the haplotype GA was associated with a 1.68-fold increase in the risk of HCC.Our results showed that the PON1 rs705382 SNP might be a risk factor for CHB in Guangxi populations.

EGF +61A/G polymorphism contributes to increased gastric cancer risk: evidence from a meta-analysis

BackgroundEpidermal growth factor (EGF) plays a pivotal role in cell proliferation, differentiation, and tumorigenesis of epithelial tissues. Variation of the EGF +61A/G (rs4444903) can lead to an alteration in EGF production and/or activity, which may result in individual susceptibility to gastric cancer. Studies investigating the association between EGF +61A/G polymorphism and gastric cancer risk produced inconsistent results. The aim of this study was to quantitatively summarize the evidence for such an association.MethodsEligible studies on the association between EGF +61A/G polymorphism and gastric cancer risk were identified by search of electronic databases including PubMed, EMBASE, Cochrane Library, and Chinese Biomedical Literature database (CBM). Data were extracted by two independent authors and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Metaregression and subgroup analyses were performed to identify the source of heterogeneity.ResultsFinally, six case–control studies with 1547 gastric cancer cases and 2762 controls were eventually identified. Overall, significant increased gastric cancer risk was found when all studies were pooled in the meta-analysis (GG vs. AA: OR = 1.438, 95% CI 1.021–2.025, P = 0.038; GG + AG vs. AA: OR = 1.256, 95% CI 1.025–1.539, P = 0.028; GG vs. AG + AA: OR = 1.265, 95% CI 1.002–1.596, P = 0.048). In subgroup analysis by ethnicity, source of control, study quality, and HWE in controls, significant increased gastric cancer risk was observed in Asians, population-based studies, high quality studies, and studies consistent with HWE. In subgroup analysis according to tumor location, and histological type, significant association was observed in all subgroups.ConclusionsThis meta-analysis suggested that the EGF +61A/G polymorphism contributes to increased gastric cancer risk, especially in Asian populations. Further well-designed studies based on large sample size in diverse populations are needed to confirm this association.