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author:("Liu, jisheng")
1.  Association between Glutathione S-Transferase T1, M1, and P1 Genotypes and the Risk of Colorectal Cancer 
Journal of Korean Medical Science  2014;29(11):1488-1492.
Glutathione S-transferases (GSTs) are enzymes which play an important role in the neutralization of toxic compounds and eradication of electrophilic carcinogens. Genetic polymorphisms within the genes encoding for GSTs may therefore cause variations in their enzyme activity, which may in turn influence the interindividual susceptibility to cancers. In this study, we aimed to investigate the association between genetic polymorphisms of GSTT1, GSTM1, and GSTP1 and the risk of colorectal cancer (CRC) in 264 cases and 317 controls in a Chinese population. Genotyping was performed by using multiplex PCR (for GSTT1 and GSTM1) and PCR-RFLP (for GSTP1) methods. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Our results showed that individuals with GSTT1 and GSTM1 null genotypes exhibited a higher risk of CRC (GSTT1, OR,1.66; 95% CI, 1.20-2.31, P=0.003; GSTM1, OR,1.57; 95% CI,1.13-2.18, P=0.007), while no association was observed for GSTP1 (Pheterozygous=0.790 or Pvariant=0.261). Furthermore, individuals who simultaneously carried the null genotypes for both GSTT1 and GSTM1 showed a stronger risk association (OR, 1.95; 95% CI, 1.33-2.85; P<0.001). In conclusion, the GSTT1 and GSTM1 polymorphisms, but not GSTP1, may modulate the CRC risk among Chinese.
Graphical Abstract
PMCID: PMC4234915  PMID: 25408579
Colorectal Neoplasms; Glutathione S-Transferase; Polymorphism; Genetic; Risk; Disease Susceptibility
2.  Association of CVD Candidate Gene Polymorphisms with Ischemic Stroke and Cerebral Hemorrhage in Chinese Individuals 
PLoS ONE  2014;9(8):e105516.
Contribution of cardiovascular disease related genetic risk factors for stroke are not clearly defined. We performed a genetic association study to assess the association of 56 previously characterized gene variants in 34 candidate genes from cardiovascular disease related biological pathways with ischemic stroke and cerebral hemorrhage in a Chinese population.
There were 1280 stroke patients (1101 with ischemic stroke and 179 with cerebral hemorrhage) and 1380 controls in the study. The genotypes for 56 polymorphisms of 34 candidate genes were determined by the immobilized probe approach and the associations of gene polymorphisms with ischemic stroke and cerebral hemorrhage were performed by logistic regression under an allelic model.
After adjusting for age, sex, BMI and hypertension status by logistic regression analysis, we found that NPPA rs5063 was significantly associated with both ischemic stroke (odds ratio [OR] 0.69; 95% confidence interval [CI], 0.52 to 0.90; P = 0.006) and cerebral hemorrhage(OR = 0.39; 95%CI, 0.19 to 0.78; P = 0.007). In addition, MTHFR rs1801133 also was associated with cerebral hemorrhage (OR = 1.48; 95%CI, 1.16 to1.89; P = 0.001) but not with ischemic stroke (OR = 1.08; 95%CI, 0.96 to1.22; P = 0.210). After false discovery rate (FDR) correction, the association of NPPA rs5063 and MTHFR rs1801133 with cerebral hemorrhage remained significant.
The NPPA rs5063 is associated with reduced risk for cerebral hemorrhage and MTHFR rs1801133 is associated with increased risk of cerebral hemorrhage in a Chinese population.
PMCID: PMC4140791  PMID: 25144711
3.  Efficacy and Safety of Valsartan/Amlodipine Single-Pill Combination in 11,422 Chinese Patients with Hypertension: an Observational Study 
Advances in Therapy  2014;31(7):762-775.
Single-pill combination (SPC) therapy of two drugs is recommended by international guidelines, including the Chinese guidelines (2010), for the treatment of hypertension in high-risk patients who require marked blood pressure (BP) reductions. Real-world data on the efficacy and safety of valsartan/amlodipine (Val/Aml) SPC are scarce. The present study is the first observational study in China to evaluate the efficacy (primary endpoint) and safety of Val/Aml (80/5 mg) SPC in Chinese patients with hypertension whose BP was not adequately controlled by monotherapy in a real-world setting.
This prospective, multicenter, open-label, post-marketing observational study included 11,422 Chinese adults (≥18 years) with essential hypertension from 238 sites of 29 provinces who were prescribed once-daily Val/Aml (80/5 mg) SPC. Patients were treated for 8 weeks. The primary efficacy variable of the study included changes in mean sitting systolic BP (MSSBP) and mean diastolic BP (MSDBP) from baseline to week 8 (end point). The secondary efficacy variable of the study included BP control rate and response rate at week 4 and 8. Safety assessments included recording and measurement of all adverse events (AEs) and vital signs in the safety population.
A significant reduction of 27.1 mmHg in MSSBP (159.6 vs. 132.5 mmHg; P < 0.0001) and 15.2 mmHg in MSDBP (95.6 vs. 80.4 mmHg; P < 0.0001) from baseline was observed at week 8. The BP-lowering efficacy of Val/Aml SPC was independent of age and comorbidities. BP control of <140/90 mmHg was achieved in 76.8% (n = 8,692) of the patients. The most frequently reported AEs were dizziness (0.2%), headache (0.2%), upper respiratory tract infection (0.2%), and edema (0.2%). Only three serious AEs were reported and they were not drug-related.
This is the first evidence-based real-world data in Chinese hypertensive patients which demonstrate the efficacy and safety of Val/Aml (80/5 mg) SPC.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0132-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4115183  PMID: 24985411
Amlodipine; Blood pressure; Cardiology; Hypertension; Single-pill combination; Valsartan
4.  Sleep duration, snoring habits and risk of acute myocardial infarction in China population: results of the INTERHEART study 
BMC Public Health  2014;14:531.
Less sleep time and snoring have been associated with cardiovascular disease (CVD) risk in Western populations; however, few studies have evaluated the different aspects of sleep duration and snoring frequency in relation to CVD, and this association has not been examined in China. The present study aimed to address the relation between sleep duration, snoring frequency and risk of acute myocardial infarction (AMI) in China population.
We conducted a hospital-based case–control study. Cases were first AMI (n = 2909). Controls were matched to cases on age and sex. 2947 controls who did not report previous angina or physical disability completed a questionnaire on sleep duration and snoring frequency. We used logistic regression to control for other risk factors.
We observed an inverse association between serious snoring frequency and AMI risk. After adjustment for all the risk factors, and the OR for everyday group and 3–5 times per week group was 1.45 (95% CI: 1.01 to 1.91) and 1.93 (95% CI: 1.52-2.46) compared to no snoring group. The OR for serious level group and moderate group was 1.77 (95% CI: 1.29 to 2.43) and 1.37 (95% CI: 1.10 to 1.69) compared to no snoring group. People having serious snoring increased 77% risk of AMI. 15.2% people in control group have ≤ 6 hours sleeping, compared with 17.4% in AMI group.
Snoring frequency, including as much as everyday and 3–5 times per week, was positively associated with AMI risk and less sleep duration was associated with risk of AMI. Less sleep time could increase AMI risk in China population.
PMCID: PMC4054902  PMID: 24885282
Cardiovascular disease; Snoring; Sleep; Acute myocardial infarction; China
5.  Common genetic variants of the human UMOD gene are functional on transcription and predict plasma uric acid in two distinct populations 
Kidney international  2013;83(4):733-740.
Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia, decreased renal excretion of UMOD and uric acid; such findings suggest a role for UMOD in the regulation of plasma uric acid. We screened common variants across the UMOD locus in two populations, one from a community-based Chinese population, the other from California twins and siblings. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK293 cells and mlMCD3 cells. By variance components in twin pairs, uric acid concentration and excretion were heritable traits. In the primary population from Beijing, we identified that carriers of haplotype GCC displayed higher plasma uric acid, and 3 UMOD promoter variants associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in an independent American population sample. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. These results suggest that UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, eventuating in elevation of plasma uric acid.
PMCID: PMC3687544  PMID: 23344472
Uromodulin; uric acid; Tamm-Horsfall protein; UMOD
6.  Genetic Variants Associated with Myocardial Infarction and the Risk Factors in Chinese Population 
PLoS ONE  2014;9(1):e86332.
Recent genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). The associations of those SNPs with myocardial infarction (MI) have not been replicated in Asian populations. Among those previously identified SNPs, we selected nine (rs10953541, rs1122608, rs12190287, rs12413409, rs1412444, rs1746048, rs3798220, rs4977574, rs579459, in or near genes 7q22, LDLR, TCF21, CYP17A1, LIPA, CXCL12, LPA, CDKN2A, ABO, respectively) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with MI and MI related risk factors in Chinese population.
Methods and Results
We conducted a case–control association study on a cohort of 2365 MI patients and 2678 unrelated controls from the Chinese population. Genotyping of 9 SNPs were performed by the TaqMan Real Time PCR method. After age, sex, and BMI adjustment, we observed the SNPs rs12190287, rs12413409, rs1412444, rs1746048 and rs4977574, were significantly associated with MI in additive models and rs12190287, rs12413409, rs4977574 were significantly associated with phenotypes of MI at the same time. We also found three SNPs rs1122608, rs3798220 and rs579459 were significantly associated with risk factors of MI, although they had no association with MI in Chinese population.
Results of this study indicate that 5 SNPs were associated with MI and 3 SNPs were associated with associated with lipoprotein levels but not with MI in a Chinese population. The present study supports some CAD-related genes in Caucasian as important genes for MI in a Chinese population.
PMCID: PMC3903528  PMID: 24475106
7.  Does Glycemic Control Offer Similar Benefits Among Patients With Diabetes in Different Regions of the World? 
Diabetes Care  2011;34(12):2491-2495.
Participants in ADVANCE were drawn from many countries. We examined whether the effects of intensive glycemic control on major outcomes in ADVANCE differ between participants from Asia, established market economies (EMEs), and eastern Europe.
ADVANCE was a clinical trial of 11,140 patients with type 2 diabetes, lasting a median of 5 years. Demographic and clinical characteristics were compared across regions using generalized linear and mixed models. Effects on outcomes of the gliclazide modified release–based intensive glucose control regimen, targeting an HbAlc of ≤6.5%, were compared across regions using Cox proportional hazards models.
When differences in baseline variables were allowed for, the risks of primary outcomes (major macrovascular or microvascular disease) were highest in Asia (joint hazard ratio 1.33 [95% CI 1.17–1.50]), whereas macrovascular disease was more common (1.19 [1.00–1.42]) and microvascular disease less common (0.77 [0.62–0.94]) in eastern Europe than in EMEs. Risks of death and cardiovascular death were highest in eastern Europe, and the mean difference in glycosylated hemoglobin between the intensive and standard groups was lowest in EMEs. Despite these and other differences, the effects of intensive glycemic control were not significantly different (P ≥ 0.23) between regions for any outcome, including mortality, vascular end points, and severe hypoglycemic episodes.
Irrespective of absolute risk, the effects of intensive glycemic control with the gliclazide MR-based regimen used in ADVANCE were similar across Asia, EMEs, and eastern Europe. This regimen can safely be recommended for patients with type 2 diabetes in all of these regions.
PMCID: PMC3220831  PMID: 21972410
8.  Methylenetetrahydrofolate reductase C677T polymorphism is associated with estimated glomerular filtration rate in hypertensive Chinese males 
BMC Medical Genetics  2012;13:74.
Plasma level of total homocysteine (tHcy) is negatively correlated with kidney function in general population. However, the causal mechanism of this correlation is poorly understood. The purpose of this study is to investigate the association of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, which is a major genetic determinant of the plasma tHcy level, with estimated glomerular filtration rate (eGFR) in Chinese.
A total of 18 814 hypertensive patients (6 914 males, 11 900 females) were included in the study.
Association between the eGFR and MTHFR C677T genotype was examined by sex-specific regression analyses. In males, TT genotype was associated with 1.37 ml/min/1.73 m2 decrease in eGFR (p = 0.004) and with an increased risk (OR = 1.32, p = 0.008) for the lowest quintile of eGFR after adjusting for age, BMI, and blood pressures. However, such association was not observed in females (p > 0.05). This association suggests MTHFR C677T polymorphism may play a role in the regulation of eGFR in males.
MTHFR 677 T is a risk allele for decreased kidney function in Chinese males, implicating this gene in the pathogenesis of chronic kidney disease (CKD).
PMCID: PMC3458982  PMID: 22897803
MTHFR C677T polymorphism; eGFR; CKD
9.  Association of inflammatory gene polymorphisms with ischemic stroke in a Chinese Han population 
Inflammatory mechanisms are important in stroke risk, and genetic variations in components of the inflammatory response have been implicated as risk factors for stroke. We tested the inflammatory gene polymorphisms and their association with ischemic stroke in a Chinese Han population.
A total of 1,124 ischemic stroke cases and 1,163 controls were genotyped with inflammatory panel strips containing 51 selected inflammatory gene polymorphisms from 35 candidate genes. We tested the genotype-stroke association with logistic regression model.
We found two single nucleotide polymorphisms (SNPs) in CCL11 were associated with ischemic stroke. After adjusting for multiple testing using false discovery rate (FDR) with a 0.20 cut-off point, CCL11 rs4795895 remained statistically significant. We further stratified the study population by their hypertension status. In the hypertensive group, CCR2 rs1799864, CCR5 rs1799987 and CCL11 rs4795895 were nominally associated with increased risk of stroke. In the non-hypertensive group, CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 and CCL11 rs4795895 were associated with ischemic stroke. After correction for multiple testing, CCR2 rs1799864 and CCR5 rs1799987 remained significant in the hypertensive group, and CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 remained significant in the non-hypertensive group.
Our results indicate that inflammatory genetic variants are associated with increased risk of ischemic stroke in a Chinese Han population, particularly in non-hypertensive individuals.
PMCID: PMC3464807  PMID: 22769019
Association study; Hypertension; Inflammatory gene; Ischemic stroke
10.  Marital Status, Education, and Risk of Acute Myocardial Infarction in Mainland China: The INTER-HEART Study 
Journal of Epidemiology  2012;22(2):123-129.
We investigated the effects of marital status and education on the risk of acute myocardial infarction (AMI) in a large-scale case-control study in China.
This study was part of the INTER-HEART China case-control study. The main outcome measure was first AMI. Incident cases of AMI and control patients with no past history of heart disease were recruited. Controls were matching by age (±5 years) and sex. Marital status was combined into 2 categories: single and not single. Education level was classified into 2 categories: 8 years or less and more than 8 years.
From 1999 to 2002, we recruited 2909 cases and 2947 controls from 17 cities. After adjustment for age, sex, BMI, psychosocial factors, lifestyle, other factors, and mutually for other risk factors, the odds ratio (OR) for AMI associated with being single was 1.51 (95% confidence interval: 1.18–1.93) overall, 1.19 (0.84–1.68; P = 0.072) in men and 2.00 (1.39–2.86; P < 0.0001) in women. The interaction of sex and marital status was statistically significant (P = 0.045). Compared with a high education level, a low education level increased the risk of AMI (1.45, 1.26–1.67); the odds ratios in men and women were 1.29 (1.09–1.52) and 1.55 (1.16–2.08), respectively. Single women with a low education level had a high risk of AMI (2.95, 1.99–4.37).
Being single was consistently associated with an increased risk for AMI, particularly in women. In addition, as compared with high education level, low education level was associated with a higher risk of AMI in both men and women.
PMCID: PMC3798590  PMID: 22245707
acute myocardial infarction; marital status; level of education; case control study; coronary heart disease
11.  Low-Temperature Preparation of Superparamagnetic CoFe2O4 Microspheres with High Saturation Magnetization 
Nanoscale Research Letters  2010;5(11):1817-1821.
Based on a low-temperature route, monodispersed CoFe2O4 microspheres (MSs) were fabricated through aggregation of primary nanoparticles. The microstructural and magnetic characteristics of the as-prepared MSs were characterized by X-ray diffraction/photoelectron spectroscopy, scanning/transmitting electron microscopy, and vibrating sample magnetometer. The results indicate that the diameters of CoFe2O4 MSs with narrow size distribution can be tuned from over 200 to ~330 nm. Magnetic measurements reveal these MSs exhibit superparamagnetic behavior at room temperature with high saturation magnetization. Furthermore, the mechanism of formation of the monodispersed CoFe2O4 MSs was discussed on the basis of time-dependent experiments, in which hydrophilic PVP plays a crucial role.
PMCID: PMC2964483  PMID: 21124634
Magnetism; Nanostructure; Superparamagnetism
12.  The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China 
BMC Medical Genetics  2010;11:107.
Previous genome-wide association studies for type 2 diabetes susceptibility genes have confirmed that a common variant, rs9939609, in the fat mass and obesity associated (FTO) gene region is associated with body mass index (BMI) in European children and adults. A significant association of the same risk allele has been described in Asian adult populations, but the results are conflicting. In addition, no replication studies have been conducted in children and adolescents of Asian ancestry.
A population-based survey was carried out among 3503 children and adolescents (6-18 years of age) in Beijing, China, including 1229 obese and 2274 non-obese subjects. We investigated the association of rs9939609 with BMI and the risk of obesity. In addition, we tested the association of rs9939609 with weight, height, waist circumference, waist-to-height ratio, fat mass percentage, birth weight, blood pressure and related metabolic traits.
We found significant associations of rs9939609 variant with weight, BMI, BMI standard deviation score (BMI-SDS), waist circumference, waist-to-height ratio, and fat mass percentage in children and adolescents (p for trend = 3.29 × 10-5, 1.39 × 10-6, 3.76 × 10-6, 2.26 × 10-5, 1.94 × 10-5, and 9.75 × 10-5, respectively). No significant associations were detected with height, birth weight, systolic and diastolic blood pressure and related metabolic traits such as total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and fasting plasma glucose (all p > 0.05). Each additional copy of the rs9939609 A allele was associated with a BMI increase of 0.79 [95% Confidence interval (CI) 0.47 to 1.10] kg/m2, equivalent to 0.25 (95%CI 0.14 to 0.35) BMI-SDS units. This rs9939609 variant is significantly associated with the risk of obesity under an additive model [Odds ratio (OR) = 1.29, 95% CI 1.11 to 1.50] after adjusting for age and gender. Moreover, an interaction between the FTO rs9939609 genotype and physical activity (p < 0.001) was detected on BMI levels, the effect of rs9939609-A allele on BMI being (0.95 ± 0.10), (0.77 ± 0.08) and (0.67 ± 0.05) kg/m2, for subjects who performed low, moderate and severe intensity physical activity.
The FTO rs9939609 variant is strongly associated with BMI and the risk of obesity in a population of children and adolescents in Beijing, China.
PMCID: PMC2914647  PMID: 20598163
13.  A Meta-Analysis of Candidate Gene Polymorphisms and Ischemic Stroke in Six Study Populations: Association of Lymphotoxin-alpha in Non-hypertensive Patients 
Background and Purpose
Ischemic stroke is a multifactorial disease with a strong genetic component. Pathways including lipid metabolism, systemic chronic inflammation, coagulation, blood pressure regulation, and cellular adhesion have been implicated in stroke pathophysiology, and candidate gene polymorphisms in these pathways have been proposed as genetic risk factors.
We genotyped 105 simple deletions and single nucleotide polymorphisms from 64 candidate genes in 3550 patients and 6560 controls from six case-control association studies conducted in the United States, Europe and China. Genotyping was performed using the same immobilized probe typing system and meta-analyses were based on summary logistic regressions for each study. The primary analyses were fixed-effects meta-analyses adjusting for age and sex with additive, dominant and recessive models of inheritance.
Although seven polymorphisms showed a nominal additive association, none remained statistically significant after adjustment for multiple comparisons. In contrast, after stratification for hypertension, two lymphotoxin-alpha polymorphisms which are in strong linkage disequilibrium were significantly associated among non-hypertensive individuals: for LTA 252A>G (additive model), OR=1.41 with 95% CI, 1.20 to 1.65, p=0.00002; for LTA 26Thr>Asn, OR 1.19 with 95% CI, 1.06 to 1.34, p=0.003. LTA 252A>G remained significant after adjustment for multiple testing using either the false discover rate or by permutation testing. The two SNPs showed no association in hypertensive subjects (eg, LTA 252A>G, OR=0.93; 95%CI, 0.84 to 1.03, p=0.17).
These observations may indicate an important role of LTA-mediated inflammatory processes in the pathogenesis of ischemic stroke.
PMCID: PMC2757095  PMID: 19131662
ischemic stroke; hypertension; inflammation; genetics

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