Association between single nucleotide variants of vascular endothelial growth factor A and the risk of thyroid carcinoma and nodular goiter in a Han Chinese population.

The aim of the present study was to investigate whether genetic variants in the vascular endothelial growth factor A gene (VEGFA) were risk factors for papillary thyroid carcinoma (PTC) or nodular goiter (NG) in Han Chinese. A total of 2,319 subjects (861 PTC patients, 562 NG patients, and 896 healthy controls) were included. Five tag single nucleotide polymorphisms (tagSNPs: rs3024997, rs3025040, rs833070, rs25648, and rs10434) in VEGFA were genotyped. SNP rs3025040 T allele was associated with a decreased risk of NG (P<0.05). SNP rs3024997 was associated with an increased risk of PTC (P<0.05) and NG (P<0.001) when an over-dominant model (AA+GG vs. AG) was considered. PTC patients carry the less frequent TT genotype (compared to the CC genotype) (P <0.05) of SNP rs3025040. Likewise, NG patients have the less frequent TC genotype compared to the CC (P <0.05). No significant association of SNPs rs833070, rs25648, and rs10434 with PTC or NG was observed. Haplotypes AT (rs3024997 and rs3025040) and GTA (rs10434, rs3025040, and rs3024997) showed a lower risk for NG (P <0.01 and P <0.05, respectively), while haplotypes GTT (rs833070, rs3025040, and rs3024997) and GGGT (rs833070, rs10434, rs3024997, and rs3025040) predicted the risk of progression to NG (both P <0.05). Haplotype AGAC (rs833070, rs10434, rs3024997, and rs3025040) conferred protection for PTC (P <0.05). In summary, this study indicated for the first time that SNPs rs3024997 and rs3025040 in VEGFA were significantly associated with PTC and/or NG. Haplotypes of the VEGFA may influence the risk of PTC and NG.

Interactions of Environmental Factors and APOA1-APOC3-APOA4-APOA5 Gene Cluster Gene Polymorphisms with Metabolic Syndrome.

OBJECTIVE: The present study investigated the prevalence and risk factors for Metabolic syndrome. We evaluated the association between single nucleotide polymorphisms (SNPs) in the apolipoprotein APOA1/C3/A4/A5 gene cluster and the MetS risk and analyzed the interactions of environmental factors and APOA1/C3/A4/A5 gene cluster polymorphisms with MetS. METHODS: A study on the prevalence and risk factors for MetS was conducted using data from a large cross-sectional survey representative of the population of Jilin Province situated in northeastern China. A total of 16,831 participations were randomly chosen by multistage stratified cluster sampling of residents aged from 18 to 79 years in all nine administrative areas of the province. Environmental factors associated with MetS were examined using univariate and multivariate logistic regression analyses based on the weighted sample data. A sub-sample of 1813 survey subjects who met the criteria for MetS patients and 2037 controls from this case-control study were used to evaluate the association between SNPs and MetS risk. Genomic DNA was extracted from peripheral blood lymphocytes, and SNP genotyping was determined by MALDI-TOF-MS. The associations between SNPs and MetS were examined using a case-control study design. The interactions of environmental factors and APOA1/C3/A4/A5 gene cluster polymorphisms with MetS were assessed using multivariate logistic regression analysis. RESULTS: The overall adjusted prevalence of MetS was 32.86% in Jilin province. The prevalence of MetS in men was 36.64%, which was significantly higher than the prevalence in women (29.66%). MetS was more common in urban areas (33.86%) than in rural areas (31.80%). The prevalence of MetS significantly increased with age (OR = 8.621, 95%CI = 6.594-11.272). Mental labor (OR = 1.098, 95%CI = 1.008-1.195), current smoking (OR = 1.259, 95%CI = 1.108-1.429), excess salt intake (OR = 1.252, 95%CI = 1.149-1.363), and a fruit and dairy intake less than 2 servings a week were positively associated with MetS (P<0.05). A family history of diabetes (OR = 1.630, 95%CI = 1.484-1.791), cardiovascular disease or cerebral diseases (OR = 1.297, 95%CI = 1.211-1.389) was associated with MetS. APOA1 rs670, APOA5 rs662799 and rs651821 revealed significant differences in genotype distributions between the MetS patients and control subjects. The minor alleles of APOA1 rs670, APOA5 rs662799 and rs651821, and APOA5 rs2075291 were associated with MetS (P<0.0016). APOA1 rs5072 and APOC3 rs5128, APOA5 rs651821 and rs662799 were in strong linkage disequilibrium to each other with r2 greater than 0.8. Five haplotypes were associated with an increased risk of MetS (OR = 1.23, 1.58, 1.80, 1.90, and 1.98). When we investigated the interactions of environmental factors and APOA1/C3/A4/A5 gene cluster gene polymorphisms, we found that APOA5 rs662799 had interactions with tobacco use and alcohol consumption (PGE<0.05). CONCLUSIONS: There was a high prevalence of MetS in the northeast of China. Male gender, increasing age, mental labor, family history of diabetes, cardiovascular disease or cerebral diseases, current smoking, excess salt intake, fruit and dairy intake less than 2 servings a week, and drinking were associated with MetS. The APOA1/C3/A4/A5 gene cluster was associated with MetS in the Han Chinese. APOA5 rs662799 had interactions with the environmental factors associated with MetS.

Association Analysis of MET Gene Polymorphism with Papillary Thyroid Carcinoma in a Chinese Population.

To investigate the association of MET SNPs with gender disparity in thyroid tumors, as well as the metastasis and prognosis of patients, 858 patients with papillary thyroid carcinoma (PTC), 556 patients with nodular goiter, and 896 population-based normal controls were recruited. The genotyping of MET SNPs was carried out using the Sequenom MassARRAY system. The distribution of MET SNPs (rs1621 and rs6566) was different among groups. Gender stratification analysis revealed a significant association between the rs1621 genotype and PTC in female patients (P = 0.037), but not in male patients (P > 0.05). For female patients, the rs1621 AG genotype was significantly higher in patients with PTC than in normal controls (P = 0.01) and revealed an increasing risk of PTC (OR: 1.465, 95% CI: 1.118-1.92). However, association analysis of the rs1621 genotype with metastasis and prognosis revealed no significant correlation in both male and female patients. The findings of our study showed that polymorphism of SNP locus rs1621 in MET gene may be associated with gender disparity in PTC. Higher AG genotypes in rs1621 were correlated with PTC in female patients, but not in male patients.

Association of Pre-miR-146a rs2910164 Polymorphism with Papillary Thyroid Cancer.

The incidence rate of papillary thyroid cancer (PTC) has increased over the past decades, but the pathogenesis remains unclear. rs2910164, located in pre-miR-146a, has been studied in PTCs with different ethnicity, but the results were inconsistent. Here we evaluate the association between rs2910164 polymorphism and PTC and investigate the effect of this polymorphism on patients' clinicopathological characteristics. 1238 PTC patients and 1275 controls, all Han population, from Northern China, were included in our study. rs2910164 was genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). Analysis of inheritance model was performed using the SNPStats program. Strength of association was assessed by odds ratio (OR) and 95% confidence interval (CI). Overall, no statistical difference in rs2910164 genotype distribution and allelic frequencies between cases and controls was found, and patients with different genotypes had similar clinicopathological characteristics in terms of stage, location, concurrent of benign thyroid tumor, and thyroiditis, while, as the number of G alleles increased, proportion of patients aged ≥45 years and those without metastasis increased (P trend < 0.001 and P trend = 0.003, resp.). However, no association remained significant after Bonferroni correction under any model of inheritance. Our results suggest no association between rs2910164 polymorphism with PTC and patients' clinicopathological characteristics.

Prevalence and Associated Factors of Passive Smoking among Women in Jilin Province, China: A Cross-Sectional Study.

BACKGROUND: The present study aimed to investigate the prevalence and associated socio-demographic factors of passive smoking among women in Jilin Province, China. METHODS: A cross-sectional study was conducted in 2012, using a self-reported questionnaire interview. A representative sample of 9788 non-smoking women aged 18-79 years was collected in Jilin Province of China by a multistage stratified random cluster sampling design. Descriptive data analysis and 95% confidence intervals (CI) of prevalence/frequency were conducted. Multivariable logistic regressions were used to examine the associated socio-demographic factors of passive smoking. RESULTS: The overall prevalence of passive smoking among non-smoking women in Jilin Province was 60.6% (95% CI: 59.3-61.8), 58.3% (95% CI: 56.7-59.9) from urban areas, and 63.4% (95% CI: 61.6-65.3) from rural areas. Twenty-six percent (95% CI: 24.9-27.1) of the non-smoking women reported daily passive smoking, of which 42.9% (95% CI: 41.6-44.1) reported passive smoking at home, and 5.1% (95% CI: 4.5-5.7) reported passive smoking in restaurants. Women in urban areas were less likely to be passive smokers than those in rural ones (OR-Odds Ratio: 0.825, 95% CI: 0.729-0.935), elderly women were less likely to be passive smokers than younger women (55-64 years OR: 0.481, 95% CI: 0.342-0.674; 65-79 years OR: 0.351, 95% CI: 0.241-0.511). Seperated/divorced women were less likely to be passive smokers (OR: 0.701, 95% CI: 0.500-0.982), and widowed women (OR: 0.564, 95%CI: 0.440-0.722), as the married were the reference group. Retired women second-hand smoked due to environmental causes significantly less than manual workers (OR: 0.810, 95% CI: 0.708-0.928). Women with a monthly family income of more than 5000 RMB were less likely to be passive smokers than those with an income less than 500 RMB (OR: 0.615, 95% CI: 0.432-0.876). CONCLUSIONS: The prevalence of passive smoking is lower than that reported in 2010 Global Adult Tobacco Survey (GATS) China, but passive smoking is still prevalent and has been an acute public health problem among non-smoking women in Jilin Province, China. Our findings suggest an urgent need for tobacco control and the efforts of public health should be both comprehensive and focus on high-risk populations in Jilin Province, China.

Rural-urban differences in the prevalence of chronic disease in northeast China.

Rural-urban differences in the prevalence of chronic diseases in the adult population of northeast China are examined. The Jilin Provincial Chronic Disease Survey used personal interviews and physical measures to research the presence of a range of chronic diseases among a large sample of rural and urban provincial residents aged 18 to 79 years (N = 21 435). Logistic regression analyses were used. After adjusting for age and gender, rural residents had higher prevalence of hypertension, chronic ischemic heart disease, cerebrovascular disease, chronic low back pain, arthritis, chronic gastroenteritis/peptic ulcer, chronic cholecystitis/gallstones, and chronic lower respiratory disease. Low education, low income, and smoking increased the risk of chronic diseases in rural areas. Reducing rural-urban differences in chronic disease presents a formidable public health challenge for China. The solution requires focusing attention on issues endemic to rural areas such as poverty, lack of chronic disease knowledge, and the inequality in access to primary care.

Association of ATM Gene Polymorphism with PTC Metastasis in Female Patients.

Ataxia telangiectasia mutated (ATM) gene is critical in the process of recognizing and repairing DNA lesions and is related to invasion and metastasis of malignancy. The incidence rate of papillary thyroid cancer (PTC) has increased for several decades and is higher in females than males. In this study, we want to investigate whether ATM polymorphisms are associated with gender-specific metastasis of PTC. 358 PTC patients in Northern China, including 109 males and 249 females, were included in our study. Four ATM single nucleotide polymorphisms (SNPs) were genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). Association between genotypes and the gender-specific risk of metastasis was assessed by odds ratios (OR) and 95% confidence intervals (CI) under the unconditional logistic regression analysis. Significant associations were observed between rs189037 and metastasis of PTC in females under different models of inheritance (codominant model: OR = 0.15, 95% CI 0.04-0.56, P = 0.01 for GA versus GG and OR = 0.08, 95% CI 0.01-0.74, P = 0.03 for AA versus GG, resp.; dominant model: OR = 0.49, 95% CI 0.25-0.98, P = 0.04; overdominant model: OR = 0.47, 95% CI 0.25-0.89, P = 0.02). However, no association remained significant after Bonferroni correction. Our findings suggest a possible association between ATM rs189037 polymorphisms and metastasis in female PTCs.

Are the SNPs of NKX2-1 associated with papillary thyroid carcinoma in the Han population of Northern China?

Papillary thyroid carcinoma (PTC) is one of the most common tumors of the thyroid gland. The common risk factors of PTC include ionizing radiation, positive family history, and thyroid nodular disease. PTC was identified in Europeans by conducting a genome-wide association study, and a strong association signal with PTC was observed in rs944289 and NKX2-1 (located at the 14q13.3 locus), which was probably the genetic risk factor of PTC. This study aimed to examine the association of this gene with PTC in Chinese. A total of 354 patients with PTC and 360 healthy control subjects from the Han population of Northern China were recruited in the study. These individuals were genotyped to determine rs12589672, rs12894724, rs2076751, and rs944289. The association of rs944289 with PTC was obtained (C vs. T, P = 0.027, OR = 1.264, 95% CI = 1.026 - 1.557; and C/C - C/T vs. T/T, P = 0.034, OR = 1.474, 95% CI = 1.028 - 2.112). Conducting a subgroup analysis, we found a marginal difference in the allele frequency distribution of rs944289 (adjusted P = 0.062) between the patients with PTC and multi-nodular goiter and the control subjects. We also observed an interaction (P = 0.029; OR = 2.578, 95% CI = 1.104 - 6.023) between rs944289 and diabetes in patients with PTC. In conclusion, rs944289 was associated with an increased risk of PTC in the Han population of Northern China, but no clear association was observed in either of the tag single nucleotide polymorphisms of NKX2-1.

Association of the ATM gene polymorphisms with papillary thyroid cancer.

Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, yet few genetic markers of PTC risk useful for screening exist. Our study aimed to evaluate the association between single nucleotide polymorphisms (SNPs) of the ataxia telangiectasia mutated (ATM) gene and PTC risk. 358 patients with PTC and 360 healthy controls were included in the case-control study. Four ATM SNPs (rs664677, rs373759, rs4988099, and rs189037) were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). The analysis of genetic data was performed using the SNPStats program. The allele frequencies and genotype distributions of the four ATM SNPs were not different between PTC patients and controls. We did not observe any tendency of increasing the frequency of the risk allele from controls, patients without metastasis to patients with metastasis (P(trend) > 0.05). Interestingly, the AG genotype of rs373759 was associated with PTC risk under an overdominant model of inheritance (adjusted OR = 1.38; 95 % CI, 1.03-1.87; P = 0.03). No haplotype was observed to be significantly associated with PTC risk. Our results suggest that heterozygosity for the ATM rs373759 polymorphism may be a potential risk factor for PTC.

Troglitazone induced apoptosis via PPARγ activated POX-induced ROS formation in HT29 cells.

OBJECTIVE: In order to investigate the potential mechanisms in troglitazone-induced apoptosis in HT29 cells, the effects of PPARγ and POX-induced ROS were explored. METHODS: [3- (4, 5)-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay, Annexin V and PI staining using FACS, plasmid transfection, ROS formation detected by DCFH staining, RNA interference, RT-PCR & RT-QPCR, and Western blotting analyses were employed to investigate the apoptotic effect of troglitazone and the potential role of PPARγ pathway and POX-induced ROS formation in HT29 cells. RESULTS: Troglitazone was found to inhibit the growth of HT29 cells by induction of apoptosis. During this process, mitochondria related pathways including ROS formation, POX expression and cytochrome c release increased, which were inhibited by pretreatment with GW9662, a specific antagonist of PPARγ. These results illustrated that POX upregulation and ROS formation in apoptosis induced by troglitazone was modulated in PPARγ-dependent pattern. Furthermore, the inhibition of ROS and apoptosis after POX siRNA used in troglitazone-treated HT29 cells indicated that POX be essential in the ROS formation and PPARγ-dependent apoptosis induced by troglitazone. CONCLUSION: The findings from this study showed that troglitazone-induced apoptosis was mediated by POX-induced ROS formation, at least partly, via PPARγ activation.

A study of the PEMT gene in schizophrenia.

The phospholipid hypothesis of schizophrenia is becoming popular because of the findings from the niacin flush test, the treatment with polyunsaturated fatty acids (PUFAs), biochemical studies for the phospholipid metabolism pathway and genetic studies of phospholipase A2. The present study attempted to investigate the gene coding for phosphatidylethanolamine N-methyltransferase (PEMT), which is an important enzyme for the synthesis of membrane phospholipids. We recruited 271 Chinese parent-offspring trios of Han descent and detected 3 single nucleotide polymorphisms (SNPs) at the PEMT locus. The transmission disequilibrium test (TDT) showed allelic association for rs464396 (X2=9.4, P=0.002), but not for the other two. The 2-SNP haplotype analysis showed haplotypic association for both the rs936108-rs464396 haplotypes (X2=25.7, d.f.=3, P=0.00001) and the rs464396-rs4244593 haplotypes (X2=17.3, d.f.=3, P=0.0006). The 3-SNP haplotype analysis also showed a haplotypic association (X2=24.4, d.f.=7, P=0.0006). The present results suggest that the PEMT gene may contribute to the etiology of schizophrenia.

Mechanisms involved in ceramide-induced cell cycle arrest in human hepatocarcinoma cells.

AIM: To investigate the effect of ceramide on the cell cycle in human hepatocarcinoma Bel7402 cells. Possible molecular mechanisms were explored. METHODS: [3- (4, 5)-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay, plasmid transfection, reporter assay, FACS and Western blotting analyses were employed to investigate the effect and the related molecular mechanisms of C2-ceramide on the cell cycle of Bel7402 cells. RESULTS: C2-ceramide was found to inhibit the growth of Bel7402 cells by inducing cell cycle arrest. During the process, the expression of p21 protein increased, while that of cyclinD1, phospho-ERK1/2 and c-myc decreased. Furthermore, the level of CDK7 was downregulated, while the transcriptional activity of PPARgamma was upregulated. Addition of GW9662, which is a PPARgamma specific antagonist, could reserve the modulation action on CDK7. CONCLUSION: Our results support the hypothesis that cell cycle arrest induced by C2-ceramide may be mediated via accumulation of p21 and reduction of cyclinD1 and CDK7, at least partly, through PPARgamma activation. The ERK signaling pathway was involved in this process.

Ceramide induces apoptosis via a peroxisome proliferator-activated receptor gamma-dependent pathway.

Both of ceramide and PPARgamma ligand can trigger cancer cell apoptosis. We here show that C2-ceramide can modulate PPARgamma expression level and its transcriptional activity and results in apoptosis in HT29 cells. Administration of PPARgamma specific antagonist GW9662 partially prevents HT29 cells from apoptosis. Furthermore, MAP kinase pathway provided a potential modulation mechanism for PPARgamma pathway related with ceramide. Our results are the first to demonstrate that C2-ceramide induces apoptosis via a PPARgamma-dependent pathway.

A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia.

This work reviewed all the reports on the NOTCH4 gene in schizophrenia, which have been published since the gene was found to be associated with illness among a British population in 2000. The results from independent studies were inconsistent. Allelic heterogeneity, clinical diagnosis, ethnical backgrounds, and linkage disequilibrium (LD) structures in the human genome may be major reasons for poor replication. A couple of studies suggested that the NOTCH4 gene could play a role in a subgroup of the disease, such as early-onset schizophrenia and negative symptoms. A single study revealed a weak association of the NOTCH4 gene with frontal lobe brain volumes and a strong association with frontal lobe cognitive performance. A meta-analysis showed stronger evidence of the NOTCH4 association in family-based studies than in case-control studies. In a previous study, we found that rs520692, a single nucleotide polymorphism (SNP) at the NOTCH4 locus, was associated with schizophrenia in a Chinese population. In the present study, we applied a large sample size to re-evaluate our initial findings and then confirmed the rs520692 association with illness. The pairwise measures did not show strong LD between paired SNPs although the SNPs tested are located within a 34-kb region, suggesting that LD within the NOTCH4 gene has been broken rapidly by historical recombination in the Chinese population. Taken together, the NOTCH4 gene may be associated with schizophrenia but how the gene contributes to the etiology of the illness needs a further investigation.

[Inhibiton of conjugated linoleic acid isomers on the proliferation of tumor cells].

OBJECTIVE: To study the effect of five conjugated linoleic acid isomers on the proliferation of human tumor cell AGS and Bel7402. METHODS: AGS, Bel7402 and Lovo cells incubated in vitro were used as model. The cell visibility was investigated after treatment with conjugated linoleic acid (CLA). RESULTS: All the five isomers had inhibitory ability to AGS, Bel7402 and Lovo cell proliferation, and the effect on AGS was more effective than that on Bel7402 and Lovo. The inhibitory effect was dose-dependent. CONCLUSION: The five isomers of CLA exhibited proliferation inhibitory effect on the tumor cell of AGS and Be17402.

Is NOTCH4 associated with schizophrenia?

The NOTCH4 locus was reported to be associated with schizophrenia in our previous study but the subsequent replication by other workers has been inconsistent. To find out possible reasons for the poor replication, the present work was undertaken to analyse four functional single nucleotide polymorphisms (SNPs) (rs367398, rs915894, rs520692 and rs422951) at the NOTCH4 locus among 141 schizophrenic family trios of Chinese Han descent. Of these four SNPs, rs520692 was the only one associated with schizophrenia (P = 0.017); the other three, however, did not show any association with the illness, including rs367398 located in the promoter region, which had shown a strong association with the illness in our previous study conducted with British samples. Although these four SNPs analysed lie within a less than 4 kb segment of genomic DNA, the pattern of linkage disequilibrium between them was unexpected. The strongest linkage disequilibrium was shown only between rs367398 and rs520692 and between rs520692 and rs422951 in both parent and patient groups. This study raises the possibility that there might be two or more disease-underlying variants at the NOTCH4 locus or at a nearby locus, and that the allelic or locus heterogeneity may be one of the possible reasons for the poor replication of the NOTCH4 finding.

[Sphingolipid and apoptosis].

Over the last decade, considerable progress has been made in the study of sphingolipids with the development of biological techniques. Sphingolipids play important roles in diverse physiological process, including cytoskeleton migration, angiogenesis, embryonic development and signal transduction. Except for this, the lastest evidence has suggested that sphingolipids and their metabolite (ceramide, sphingosine, sphingosine 1-phosphate) can induce apoptosis in a wide variety of tumor cell lines such as LoVo HT29, Bel7402, A549, CNE2 cells. This paper is attempted to review the recent advances of investigation into the relationship between sphingolipids and apoptosis.