Wei-Qing Chen

Clinical Outcome of Hyperuricemia in IgA Nephropathy: A Retrospective Cohort Study and Randomized Controlled Trial

Background: Hyperuricemia is an independent risk factor for renal progression in IgA nephropathy (IgAN). However, no study has evaluated the effect of allopurinol on the clinical outcome in hyperuricemic IgAN. Methods: First,a retrospective cohort study of 353 IgAN patients was conducted to explore the relationship between uric acid (UA) and the progression of renal disease over a mean period of 5 years. Then, 40 hyperuricemic IgAN patients were randomized to receive allopurinol (100–300 mg/day) or usual therapy for 6 months. The study outcomes were renal disease progression and/or blood pressure. Results: Hyperuricemia independently predicted renal survival at 1, 3, and 5 years after adjustment for different baseline estimated glomerular filtration rates. In the randomized controlled trial, allopurinol did not significantly alter renal progression or proteinuria. The antihypertensive drug dosage was reduced in 7 of 9 cases with hypertension in the allopurinol group compared to 0 of 9 cases in the control group (p < 0.01). UA levels correlated with mean arterial pressure in normotensive patients (r = 0.388, p < 0.001). Conclusion: Hyperuricemia predicts the progression of IgAN independently of baseline estimated glomerular filtration rate. Allopurinol may improve the control of blood pressure. Further studies are required to explore the effects of lowering UA on renal protection in IgAN.

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

The introduction of the Simian virus 40 (SV40) early region, the telomerase catalytic subunit (hTERT) and an oncogenic allele of H-Ras directly transforms primary human cells. SV40 small T antigen (ST), which forms a complex with protein phosphatase 2A (PP2A) and inhibits PP2A activity, is believed to have a critical role in the malignant transformation of human cells. Recent evidence has shown that aberrant microRNA (miRNA) expression patterns are correlated with cancer development. Here, we identified miR-27a as a differentially expressed miRNA in SV40 ST-expressing cells. miR-27a is upregulated in SV40 ST-transformed human bronchial epithelial cells (HBERST). Suppression of miR-27a expression in HBERST cells or lung cancer cell lines (NCI-H226 and SK-MES-1) that exhibited high levels of miR-27a expression lead to cell growth arrested in the G0–G1 phase. In addition, suppression of miR-27a in HBERST cells attenuated the capacity of such cells to grow in an anchorage-independent manner. We also found that suppression of the PP2A B56γ expression resulted in upregulation of miR-27a similar to that achieved by the introduction of ST, indicating that dysregulation of miR-27a expression in ST-expressing cells was mediated by the ST–PP2A interaction. Moreover, we discovered that Fbxw7 gene encoding F-box/WD repeat-containing protein 7 was a potential miR-27a target validated by dual-luciferase reporter system analysis. The inverse correlation between miR-27a expression levels and Fbxw7 protein expression was further confirmed in both cell models and human tumor samples. Fbxw7 regulates cell-cycle progression through the ubiquitin-dependent proteolysis of a set of substrates, including c-Myc, c-Jun, cyclin E1 and Notch 1. Thus, promotion of cell growth arising from the suppression of Fbxw7 by miR-27a overexpression might be responsible for the viral oncoprotein ST-induced malignant transformation. These observations demonstrate that miR-27a functions as an oncogene in human tumorigenesis.

Behavioural development of school-aged children who live around a multi-metal sulphide mine in Guangdong province, China: a cross-sectional study

BackgroundThe deleterious biological effects of low-level, long-term exposure to heavy metals are well known, and children are the most susceptible population. Dabaoshan Mine in the southeast of Guangdong Province is at high risk of discharging multi-metals pollutants into a local river (Hengshihe) and the surrounding area. The present study aimed to estimate relationships between measured multi-metal exposures and the presence of behavioural problems for the school-aged children in the polluted area.MethodsA cross-sectional study was performed. Children aged 7–16 years living in three villages of the Hengshihe area with different degrees of heavy-metal pollution participated in this study. Local environmental samples (water and crops) and childrens hair were collected, and concentrations of heavy metals were determined. The Child Behaviour Check-list (CBCL) was used to assess the presence of behaviour problems. General linear regression was used to analyze the contribution of hair metals to each CBCL subscale with adjustment for socio-demographic confounding factors.ResultsMultiple regression analyses revealed significant effects of hair lead, cadmium and zinc levels on CBCL subscales. Log-transformed hair lead, cadmium and zinc levels accounted for an incremental of 8% to 15% variance in anxious/depressed, withdrawn, somatic complaints, social problems, thought problems, attention problems, delinquent behaviour and aggressive behaviour. The concurrent log-transformed hair lead and zinc levels were strongly associated with all subscales while the concurrent log-transformed hair cadmium was only significantly associated with withdrawn, social problems and attention problems.ConclusionThis study reveals that heavy metal exposure was associated with increased risk of behavioral problems for school-aged children.

Cancer mortality in a Chinese population surrounding a multi-metal sulphide mine in Guangdong province: an ecologic study

BackgroundThe Dabaoshan mine in the southeast of Guangdong Province, China, is at high risk of multi-metal pollutant discharge into a local river (Hengshihe) and the surrounding area. Following approximately 30 years of exposure to these metals, little is known regarding the subsequent health effects and risks for the local residents. In our present study, we have estimated the relationships between long-term environmental exposure to multiple heavy metals and the risk of cancer mortality in a Chinese population in the vicinity of Dabaoshan.MethodsAn ecologic study was performed. Between 2000-2007, a total population of 194,131 lived in the nine agricultural villages that surround the Hengshihe area. Heavy metals concentrations were determined in local environmental samples (water and crops) and whole blood taken from 1152 local residents of both a high-exposure area (HEA) and a low-exposure area (LEA). We calculated the rate ratio and standardized mortality ratios based on age- and gender-specific cancer mortality rates for the different reference populations (based on district, county and province). Simple, multiple linear and ridge regression models were used to evaluate the associations between exposure to multiple heavy metals and cancer mortality in the nine villages, after adjustment for age and sex.ResultsThe geometric mean blood levels of cadmium and lead were measured at 24.10 μg/L and 38.91 μg/dL for subjects (n = 563) in the HEA and 1.87 μg/L and 4.46 μg/dL for subjects (n = 589) from the LEA, respectively (P < 0.001). The rate of mortality from all cancers in the HEA was substantially elevated in comparison with the corresponding mortality rate in the LEA for men (rate ratio = 2.13; 95% confidence intervals = 1.63 - 2.77) and women (2.83; 1.91 - 4.19); rates were also significantly elevated compared with the rate when compared to the entire Wengyuan County area, or the provincial reference population. In addition, mortality rates were significantly increased for stomach, lung and esophageal cancer in the HEA in comparison with the corresponding rates in the LEA, in Wengyuan County and the provincial reference population for men, women and both combined. Further analysis showed that there were significantly positive correlations between exposure to cadmium and lead and the risk of all-cancers and stomach cancer mortality among women and both sexes, whilst zinc exposure showed no association with the risk of site-specific cancer mortality in the nine villages evaluated.ConclusionsThe findings of this study reveal probable associations between long-term environmental exposure to both cadmium and lead and an increased risk of mortality from all cancer, as well as from stomach, esophageal and lung-cancers.

α4 is highly expressed in carcinogen-transformed human cells and primary human cancers.

A regulator of the protein phosphatase 2A (PP2A), α4, has been implicated in a variety of functions that regulate many cellular processes. To explore the role of α4 in human cell transformation and tumorigenesis, we show that α4 is highly expressed in human cells transformed by chemical carcinogens including benzo(a)pyrene, aflatoxin B1, N-methyl-N′-nitro-N-nitrosoguanidine, nickel sulfate and in several hepatic and lung cancer cell lines. In addition, overexpression of α4 was detected in 87.5% (74/80) of primary hepatocellular carcinomas, 84.0% (21/25) of primary lung cancers and 81.8% (9/11) of primary breast cancers, indicating that α4 is ubiquitously highly expressed in human cancer. Functional studies revealed that elevated α4 expression results in an increase in cell proliferation, promotion of cell survival and decreased PP2A-attributable activity. Importantly, ectopic expression of α4 permits non-transformed human embryonic kidney cells (HEKTER) and L02R cells to form tumors in immunodeficient mice. Furthermore, we show that the highly expressed α4 in transformed cells or human tumors is not regulated by DNA hypomethylation. A microRNA, miR-34b, that suppresses the expression of α4 through specific binding to the 3′-untranslated region of α4 is downregulated in transformed or human lung tumors. Taken together, these observations identify that α4 possesses an oncogenic function. Reduction of PP2A activity due to an enhanced α4–PP2A interaction contributes directly to chemical carcinogen-induced tumorigenesis.

Associations of CYP2A6 genotype with smoking behaviors in southern China

AIMS To investigate the association of CYP2A6 genetic polymorphisms with smoking-related phenotypes in Chinese smokers. DESIGN Case-only genetic association study. SETTING Southern China. PARTICIPANTS A total of 1328 Han Chinese smokers who participated in a community-based chronic disease screening project in Guangzhou and Zhuhai from 2006 to 2007. MEASUREMENTS All participants answered a structured questionnaire about socio-demographic status and smoking behaviors and informative alleles were genotyped for the cytochrome P450 2A6 (CYP2A6) gene (CYP2A6*4,*5,*7,*9 and *10). FINDINGS The frequencies of CYP2A6*4, *5, *7, *9 and *10 alleles were 8.5, 1.2, 6.3, 13.5 and 2.4%, which corresponded to 48.9, 15.4, 24.2 and 11.5% of participants being classified as normal, intermediate, slow and poor metabolizers, respectively. Multivariate analyses in male smokers demonstrated that compared with normal metabolizers, poor metabolizers reported smoking fewer cigarettes per day [adjusted odds ratio (OR) = 0.49; 95% confidence interval (CI): 0.32-0.76], started smoking regularly later in life (adjusted OR = 1.55; 95% CI: 1.06-2.26) and, among former smokers, reported smoking for a shorter duration prior to quitting (adjusted OR = 0.33; 95% CI: 0.12-0.94). However, poor metabolizers were less likely to quit smoking and remain abstinent than normal metabolizers (adjusted OR = 0.54; 95% CI: 0.34-0.86). CONCLUSIONS Reduced metabolism function of cytochrome P450 2A6 in smokers appears to be associated with fewer cigarettes smoked, later initiation of smoking regularly, shorter smoking duration and lower likelihood of smoking cessation.

Prevalence and determinants of diabetes and impaired fasting glucose among urban community-dwelling adults in Guangzhou, China

AIM This study aimed to estimate the prevalence of diabetes and impaired fasting glucose (IFG) in the adult population aged >or= 20 years in Guangzhou and to evaluate the associated risk factors. METHOD A total of 6197 randomly selected adults, aged >or= 20 years and living for at least 5 years in Guangzhou, participated in questionnaire-based interviews between 2006 and 2007, and had their clinical characteristics and standard blood chemistries measured. A 75 g OGTT was conducted for those subjects with fasting glucose levels >or= 5.6 mmol/L. Diabetes and IFG were defined according to WHO 1999 criteria. RESULTS Based on Chinese census data, the age- and gender-standardized prevalences of diabetes and IFG were 5.5% and 3.3%, respectively. Among the identified diabetic individuals in the present investigation, 42.3% were newly diagnosed. The prevalence of diabetes and IFG increased with age. The results of multivariate logistic-regression analyses showed that diabetes and IFG were significantly associated with age, a family history of diabetes, obesity, hypertension and hyperlipidaemia. CONCLUSION The prevalences of diabetes and IFG have increased dramatically over the past decade. Yet, a large proportion of cases go undiagnosed. These results suggest an urgent need to establish regular population-based diabetes screening in Guangzhou.

Cigarette smoking and p16INK4α gene promoter hypermethylation in non-small cell lung carcinoma patients: a meta-analysis.

Background Aberrant methylation of promoter DNA and transcriptional repression of specific tumor suppressor genes play an important role in carcinogenesis. Recently, many studies have investigated the association between cigarette smoking and p16INK4α gene hypermethylation in lung cancer, but could not reach a unanimous conclusion. Methods and Findings Nineteen cross-sectional studies on the association between cigarette smoking and p16INK4α methylation in surgically resected tumor tissues from non-small cell lung carcinoma (NSCLC) patients were identified in PubMed database until June 2011. For each study, a 2×2 cross-table was extracted. In total, 2,037 smoker and 765 nonsmoker patients were pooled with a fixed-effects model weighting for the inverse of the variance. Overall, the frequency of p16INK4α hypermethylation was higher in NSCLC patients with smoking habits than that in non-smoking patients (OR = 2.25, 95% CI = 1.81–2.80). The positive association between cigarette smoking and p16INK4α hypermethylation was similar in adenocarcinoma and squamous-cell carcinoma. In the stratified analyses, the association was stronger in Asian patients and in the studies with larger sample sizes. Conclusion Cigarette smoking is positively correlated to p16INK4α gene hypermethylation in NSCLC patients.

Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways

OBJECTIVE To explore the interactions between smoking and CYP2A6 genotypes on type 2 diabetes (T2DM) as well as potential pathways for smoking in causing T2DM. DESIGN Cross-sectional study. METHODS A total of 1344 smokers with complete data from a community-based T2DM survey in Guangzhou and Zhuhai of China from July 2006 to June 2007 were interviewed with a structured questionnaire about socio-demographic status and daily cigarette consumption. Serum glucose, insulin, and cotinine were measured after an overnight fast. Subjects were genotyped for CYP2A6 and classified, according to genotype, into normal, intermediate, slow, or poor nicotine metabolizers based on prior knowledge of CYP2A6 allele associations with nicotine C-oxidation rate. Abdominal obesity was defined as a waist-to-hip ratio ≥0.90 for males or ≥0.85 for females. Type 2 diabetic patients (n=154) were diagnosed according to WHO 1999 criteria. Chi-square tests, multivariate logistic regression models, and a structural equation model were used in this study. RESULTS Multivariate analysis indicated that, compared with light smoking, heavy smoking significantly increased the risk of T2DM (odds ratio (OR)=1.75, 95% CI=1.01-3.05). There were significant interactions between heavy smoking and slow CYP2A6 (OR=5.12, 95% CI=1.08-24.23) and poor CYP2A6 metabolizer genotypes (OR=8.54, 95% CI=1.28-57.02) on T2DM. Structural equation modeling indicated that CYP2A6 moderation of smoking quantity risk on T2DM was mediated by the effects on serum cotinine, abdominal obesity, insulin resistance, and insulin secretion. CONCLUSIONS Heavy smoking was significantly associated with T2DM, and this association was moderated by CYP2A6 genotype and mediated by serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.

The association between smoking quantity and hypertension mediated by inflammation in Chinese current smokers.

Objectives: Previous studies indicated that cigarette smokers were more likely to develop hypertension, and both smoking and hypertension were associated with inflammation. Whether inflammation mediates the relationship of them is unclear. This study aims to examine whether inflammation mediates the association between smoking and hypertension. Methods: Nine hundred and eighty-four Chinese current smokers from a community-based chronic diseases survey in Guangzhou and Zhuhai were interviewed about sociodemographics, smoking, chronic conditions, and other health-related variables. Hypertension was defined according to 2007 European Society of Hypertension and European Society of Cardiology (ESH-ESC) Practice Guidelines. Inflammatory markers including C-reactive protein (CRP), interleukin (IL)-6, IL-1&bgr;, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-&agr; (TNF-&agr;), and vascular cell adhesion molecule-1 (VCAM-1) were measured by flow cytometry. Logistic regressions were performed to assess the mediation of inflammation on the relationship between smoking quantity and hypertension. Results: We observed a positive association between smoking quantity and hypertension (P < 0.05). After controlling for potential confounders, daily cigarette consumption was significantly associated with higher level of CRP and VCAM-1 and lower level of TNF-&agr; among six measured inflammatory markers, and the current smokers with hypertension had significantly higher level of MCP-1 and CRP than those smokers who were normotensive. Furthermore, the association between smoking quantity and hypertension was mediated by CRP, which accounted for 58.59% of the estimated causal effect of smoking on hypertension. Conclusion: We have confirmed previous observations that smoking quantity was positively associated with hypertension, and the results of our study suggested that the association between smoking and hypertension was probably mediated by CRP.