Impact of Mir196a-2 Genotypes on Colorectal Cancer Risk in Taiwan.

We aimed to investigate the association between genotypes for mir146a and mir196a-2 and the risk of developing colorectal cancer (CRC). We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the mir146a rs2910164 and mir196a-2 rs11614913 genotypes in 362 CRC patients and 362 controls. We also assessed the interactions between these genotypes and age, gender, smoking, alcohol consumption, and BMI status on CRC risk. Additionally, the serum expression level of mir196a-2 was quantified using quantitative reverse transcription-PCR. Our findings demonstrated that among the controls, the proportions of TT, CT, and CC genotypes of mir196a-2 rs11614913 were 32.3%, 48.1%, and 19.6%, respectively. As for the cases, the proportions were 24.6%, 45.0%, and 30.4%, respectively. Logistic regression analysis revealed that the CC genotype carriers had a 2.04-fold increased risk (95% confidence interval [CI] = 1.36-3.06, p = 0.0008). Furthermore, carriers of the CT + CC genotypes also exhibited a significant association with CRC risk (odds ratio [OR] = 1.46, 95% CI = 1.06-2.03, p = 0.0261). Moreover, carriers of the CC genotype had significantly higher serum levels of mir196a-2 compared to those with the TT genotype (p < 0.0001), indicating a genotype-phenotype correlation. No association was found regarding mir146a rs2910164. In conclusion, mir196a-2 rs2910164 genotypes, along with their associated expression, can serve as predictive markers for CRC risk.

Pioglitazone for primary stroke prevention in Asian patients with type 2 diabetes and cardiovascular risk factors: a retrospective study.

BACKGROUND: Studies assessing the efficacy of pioglitazone solely for primary stroke prevention in Asian patients with type 2 diabetes mellitus (DM) and present multiple cardiovascular (CV) risk factors are rare. Thus, we aimed to assess the effect of pioglitazone on primary stroke prevention in Asian patients with type 2 DM without established CV diseases but with risk factors for CV diseases. METHODS: Between 2000 and 2012, we enrolled patients aged ≥ 18 years, who were newly diagnosed with type 2 diabetes and had at least one of the following CV risk factors: hypertension and hyperlipidemia. Patients with a history of stroke and those using insulin or glucagon-like peptide-1 agonist for more than 3 months were excluded. Patients were divided into the pioglitazone and non-pioglitazone groups based on their receipt of pioglitazone during the follow-up period. Propensity-score matching (1:1) was used to balance the distribution of the baseline characteristics and medications. Follow-up was terminated upon ischemic stroke development, withdrawal from the insurance system, or on December 31, 2013, whichever occurred first. The overall incidence of new-onset ischemic stroke in the two groups was subsequently compared. The subgroup analyses of ischemic stroke were conducted using different baseline features. Additionally, the effect of pioglitazone exposure dose on the occurrence of ischemic stroke was evaluated. Chi square test, Student's t-test, competing risk regression models, Kaplan-Meier method, and log-rank test were some of the statistical tests conducted. RESULTS: A total of 13 078 patients were included in the pioglitazone and non-pioglitazone groups. Compared with patients who did not receive pioglitazone, those administered pioglitazone had a lower risk of developing ischemic stroke (adjusted hazard ratio: 0.78; 95% confidence interval: 0.62-0.95). The subgroup analyses defined by different baseline features did not reveal significant alterations in the observed effect of pioglitazone. Moreover, a significant decreasing trend in ischemic stroke risk with an increase in pioglitazone dose (p-value for trend = 0.04) was observed. CONCLUSION: Pioglitazone use decreased the risk of new-onset ischemic stroke in Asian patients with type 2 DM and CV risk factors. Trial registration number CMUH104-REC2-115-CR4.

The Contribution of DNA Ligase 4 Polymorphisms to Colorectal Cancer.

BACKGROUND/AIM: While numerous biomarkers associated with genetic susceptibility to colorectal cancer (CRC) have been identified and validated through epidemiological studies, the specific influence of DNA ligase 4 (Lig4) genotypes remains unexplored. This study aimed to elucidate the hitherto unexamined relationship between Lig4 genotypes and CRC risk. MATERIALS AND METHODS: The genotypes of Lig4 rs1805388 were determined applying the polymerase chain reaction-restriction fragment length polymorphism methodology. The potential association between these genotypes and CRC risk was assessed in a Taiwanese population comprising 362 CRC cases and an equal number of age- and sex-matched controls. RESULTS: In the genotypic analysis, the distribution of CC, CT, and TT genotypes for Lig4 rs1805388 among CRC cases was 54.7%, 38.1%, and 7.2%, respectively. This distribution was not significantly different from the controls, which exhibited genotypic frequencies of 57.2%, 36.7%, and 6.1%, respectively (p for trend=0.7314). Analysis of allelic distribution indicated that individuals carrying the T allele of Lig4 rs1805388 displayed a slightly elevated CRC risk compared to those carrying the C allele (odds ratio=1.10, 95% confidence interval=0.87-1.39, p=0.4685). CONCLUSION: The variant genotypes of Lig4 rs1805388 may not serve as predictive markers for CRC risk in the Taiwanese population.

Oral hypoglycaemic agents and the development of non-fatal cardiovascular events in patients with type 2 diabetes mellitus.

AIMS: This study aimed to assess the risk of non-fatal cardiovascular events among patients with type 2 diabetes mellitus (T2DM) who are taking metformin, glimepiride or glyburide. MATERIALS AND METHODS: Using the National Health Insurance Research database in Taiwan, this retrospective cohort study identified 1159 patients with newly diagnosed T2DM from 1998 to 2007, 30 years and older and without a history of cardiovascular disease at baseline. Patients with cancer, liver cirrhosis or chronic kidney disease were excluded. On the basis of prescription, patients were grouped into three medication subcohorts: metformin (N = 595), glimepiride (N = 234) or glyburide (N = 330) monotherapy for 100% of the follow-up period without any oral anti-diabetic agents added or changed, by the end of 2009. Incidence and hazard ratios of non-fatal cardiovascular events including coronary artery disease, peripheral artery disease, stroke and heart failure among these three subcohorts were compared. RESULTS: The overall incidence of non-fatal cardiovascular events was the highest for patients taking glyburide (169.1 per 1000 person-years), followed by for those taking glimepiride and metformin (95.2 and 49.1 per 1000 person-years, respectively). Compared with the adjusted hazard ratio for patients taking glyburide, the adjusted hazard ratio for those taking glimepiride was 0.52 (95% CI 0.40-0.69) and for those taking metformin was 0.31 (95% CI 0.24-0.40). CONCLUSIONS: T2DM patients taking metformin and glimepiride are at lower risk of non-fatal cardiovascular events than those taking glyburide.

Impact of Matrix Metalloproteinase-8 Genotypes on Colorectal Cancer Risk in Taiwan.

BACKGROUND/AIM: This study aimed to investigate the involvement of matrix metalloproteinase-8 (MMP-8) genotypes in the development of colorectal cancer (CRC). MATERIALS AND METHODS: The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to analyze the genotypes of MMP-8 C-799T (rs11225395), Val436Ala (rs34009635), and Lys460Thr (rs35866072) in 362 patients with CRC and 362 controls. Additionally, the potential associations between these genotypes and factors such as age, sex, smoking, alcohol consumption, and body mass index (BMI) status in relation to CRC risk were also assessed. RESULTS: No significant differences in the distribution of MMP-8 rs11225395 genotypes were found between the control and case groups (p for trend=0.3836). Logistic regression analysis demonstrated that individuals with the MMP-8 rs11225395 variant CT and TT genotypes had a 0.83 and 0.77-fold risk of CRC, respectively. Moreover, carriers of the rs11225395 CT+TT genotypes were not associated with CRC risk either (p=0.2063). Furthermore, individuals with the MMP-8 rs11225395 TT genotype exhibited significantly lower odds of CRC risk compared to those with the CC genotype among non-smokers (p=0.0379). No significant associations were observed with respect to MMP-8 rs34009635 or rs35866072. CONCLUSION: The analyzed genotypes of MMP-8 play a minor role in determining individual susceptibility to CRC risk.

The Significant Impacts of Interleukin-8 Genotypes on the Risk of Colorectal Cancer in Taiwan.

Interleukin-8 (IL-8), a pro-inflammatory cytokine, is upregulated in CRC and plays an important role in its development and progression. Genetic variants in the IL-8 gene may impact the risk of CRC by modulating IL-8 levels. Our primary objective was to investigate the role of IL-8 genotypes in the development of CRC. To accomplish this, we employed the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the genotypes of IL-8 rs4017, rs2227306, rs2227543, and rs1126647 in 362 CRC patients and 362 controls. Additionally, we evaluated the interactions between these genotypes and factors such as age, gender, smoking, alcohol consumption, and body mass index (BMI) status in relation to the risk of CRC. Furthermore, we utilized quantitative reverse transcription-PCR to measure the serum IL-8. The results demonstrated a significant difference in the distribution of rs4017 genotypes between the control and case groups (p for trend = 0.0059). Logistic regression analysis revealed that individuals with variant AA genotype had a 1.92-fold higher CRC risk (95% confidence interval [CI] = 1.28-2.89, p = 0.0023). Moreover, carriers of the IL-8 rs4017 AT + AA genotypes exhibited a significant association with CRC risk (odds ratio [OR] = 1.39, 95% CI = 1.02-1.91, p = 0.0460). Additionally, individuals with IL-8 rs4017 AA genotype displayed significantly elevated serum IL-8 compared to those with TT genotype at a 1.73-fold level (p < 0.0001), indicating a correlation between genotype and phenotype. In conclusion, the genotypes of IL-8 rs4017, along with their associated expression levels, can potentially serve as predictive markers for the risk of CRC.

Role of Matrix Metallopeptidase-2 Genotypes in Taiwanese Patients With Colorectal Cancer.

BACKGROUND/AIM: Matrix metalloproteinase-2 (MMP2) has been reported to plays a critical role in the metastatic behaviors of cancer via regulation of the extracellular matrix. However, its genotypes have seldom been examined in colorectal cancer (CRC). We examined the role of MMP2 promoter -1306 (rs243865) and -735 (rs2285053) genotypes in colorectal cancer (CRC). MATERIALS AND METHODS: Genotypes of MMP2 were determined by typical polymerase chain reaction-restriction fragment length polymorphism methodology in 362 CRC cases and 362 age-, sex- and behavior-matched controls. RESULTS: The genotypic analysis showed that MMP2 -1306 CT and TT genotypes were significantly associated with an increased CRC risk (odds ratios=1.41 and 3.55, 95% confidence intervals=1.02-1.96 and 1.75-7.19, and p=0.0482 and p=0.0004, respectively). The allelic frequency analysis showed that the T allele for MMP2 -1306 increased CRC risk (odds ratio=1.71, 95% confidence interval=1.32-2.23, p=4.89×105). Stratification analysis showed that MMP2 -1306 genotypes were specifically associated with alcohol drinking, and metastatic status among patients with CRC. There was no association with MMP2 -735. CONCLUSION: The MMP2 -1306 genotype serves as a novel predictive marker for CRC risk among Taiwanese, and patients who have a tendency to undergo metastasis.

The Contribution of Matrix Metalloproteinase-7 Promoter Genotypes to Hepatocellular Carcinoma Susceptibility.

BACKGROUND/AIM: Metalloproteinase-7 (MMP-7) has been previously found to be up-regulated in hepatocellular carcinoma (HCC) specimens and cells, favoring epithelial-mesenchymal transition. However, the contribution of MMP-7 genotypes to HCC has not been revealed to date. The study aimed to evaluate the contribution of MMP-7 promoter A-181G (rs11568818) and C-153T (rs11568819) genotypes on the risk of HCC in Taiwan, where HCC incidence is extremely high compared to worldwide data. MATERIALS AND METHODS: In this case-control study, MMP-7 genotypes and their association with cigarette smoking and alcohol drinking habits were determined in 298 HCC patients and 889 healthy subjects by a typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: Ever smokers and alcohol drinkers were represented with higher percentages in the case group compared to the control group. MMP-7 rs11568818 genotypes were not found differentially distributed in case and control groups (p for trend=0.5246). People of the analyzed cohort of the present study were all of CC genotypes at their rs11568819 polymorphic sites, without any CT or TT genotypes. As for gene-lifestyle interactions, people with variant genotypes at MMP-7 rs11568818 had the same odds for HCC development compared to the wild-type AA genotype, no matter whether the subjects belonged to the smoker, non-smoker alcohol drinker, or non-drinker groups. CONCLUSION: MMP-7 variant genotypes did not present any significance towards being a marker for HCC risk in Taiwanese.

Type 1 diabetes is associated with an increased risk of venous thromboembolism: A retrospective population-based cohort study.

BACKGROUND: It has been unclear whether diabetes mellitus (DM) is positively associated with a risk of venous thromboembolism (VTE). In addition, whether the risk of VTE is altered in patients with type 1 diabetes (T1DM) has rarely been explored. AIM: We investigated whether patients with T1DM are at a relatively high risk of VTE development. METHODS: We retrieved data from the National Health Insurance Research Database of Taiwan to conduct this retrospective cohort study. The T1DM group consisted of 4967 patients diagnosed as having T1DM before 2003. The non-T1DM group comprised 19 868 age- and sex-matched enrollees without T1DM. Cox proportional hazard regression analysis was used to investigate the hazard ratio of VTE in patients with T1DM relative to those without T1DM. RESULTS: During a mean follow-up period of 8.61 years, the risk of VTE in the T1DM group was 5.33-fold higher than in the non-T1DM group after adjusting for dyslipidemia, hypertension, stroke, lower leg fracture or surgery, and obesity. Further stratified analysis revealed that the risk of VTE was significantly high in both sexes and in all age groups below the age of 60. CONCLUSION: T1DM appears to be an independent risk factor for VTE development.

Association of Adiponectin Genotypes With Colorectal Cancer Susceptibility in Taiwan.

AIM: To investigate the association between adiponectin (ADIPOQ) genotypes and colorectal cancer (CRC) risk among Taiwanese. MATERIALS AND METHODS: Polymerase chain reaction-restriction fragment length polymorphism was adopted to identify ADIPOQ rs266729, rs2241766 and rs1501299 genotypes among 362 CRC patients and 362 healthy controls. RESULTS: ADIPOQ rs266729 GG genotype (p=0.0075) and G allele (p=0.0061) are associated with a significantly increased CRC risk. There is no differential distribution of rs2241766 and rs1501299 genotypes. As for the gene-lifestyle interaction, there are obvious joint effects of rs266729 genotype on the CRC risk among non-smoker, non-alcohol drinker, while not on smoker or non-drinker subgroups. No significant correlation was observed between rs266729 genotypic distributions and age, gender, tumor size, location or metastasis status. Interestingly, a correlation of rs266729 genotype and larger BMI on CRC risk was found. CONCLUSION: G allele at ADIPOQ rs266729 may serve as a determiner for CRC risk, especially for those with BMI ≥24.

Risk of macrovascular complications in statin-treated patients developing diabetes.

AIMS: To assess the risk of macrovascular complications in patients developing diabetes from statin treatment. METHODS: In this population-based cohort study, 40,409 participants who began to receive statin therapy between 2000 and 2012 were enrolled in to the study group, and another 1:1 matched adults without statin treatment during the same period served as the control group. Both groups were followed up to identify individuals who later developed diabetes. After a follow-up identification of diabetes, diabetes and non-diabetes cohorts were subjected to an analysis for the risk of macrovascular events between diagnosis of diabetes and December 31, 2013. RESULTS: Compared with individuals without statin therapy, statin-treated patients had a higher risk of developing diabetes (adjusted hazard ratio: 2.46; 95% confidence interval: 2.37-2.57). Compared with statin-treated patients without diabetes, statin-treated participants developing diabetes had a higher overall incidence of macrovascular complications (adjusted hazard ratio: 1.74; 95% confidence interval: 1.62-1.88). Moreover, compared with that of other diabetogenic statins, patients taking pravastatin had a lower risk of developing diabetes (adjusted hazard ratio: 0.63; 95% confidence interval: 0.55-0.73) and macrovascular events (adjusted hazard ratio: 0.64; 95% confidence interval: 0.42-0.98). CONCLUSIONS: According to these findings, prescribing statins that have a neutral effect on glucose homeostasis may be advisable for Asian populations.

Increased risk of new-onset type 2 diabetes in people with chronic kidney disease.

PURPOSE: This study investigated whether people with chronic kidney disease (CKD) are at the risk of new-onset type 2 diabetes. METHODS: A cohort comprising 16,624 people with CKD, and an age- and sex-matched control cohort of 66,496 persons without any clinical kidney disease were identified from the Taiwan National Health Insurance Database during the period of 2000-2010. Both cohorts were followed up to 2011 to evaluate the incidence and hazard ratio (HR) of developing new-onset type 2 diabetes. Diseases were identified based on diagnosis coding. RESULTS: The incidence of type 2 diabetes was 1.51-fold higher in the CKD cohort than in the control cohort (16.9 versus 11.2 per 1,000 person-years) with an adjusted hazard ratio of 1.17 (95% confidence interval, (CI)1.10-1.24). In the multivariate Cox regression model considering the competing-risk death, the adjusted subhazard ratio of type 2 diabetes was 1.30 (95% CI1.22-1.38) for the CKD cohort compared to the control cohort. CONCLUSIONS: People with CKD patients are at an increased risk of developing new-onset type 2 diabetes. Close surveillance for diabetes should be considered for these people.

Risk of allergic conjunctivitis in patients with type 1 diabetes mellitus: a population-based retrospective cohort study.

OBJECTIVE: In accordance with the dichotomy between T helper type 1(Th1) and T helper type 2 (Th2) responses, the occurrence of allergic conjunctivitis (AC) and type 1 diabetes mellitus (T1DM) is, in theory, inversely related in the individual. However, recent studies investigating the association between the two diseases are controversial. DESIGN: Population-based cohort study. SETTING: We used claims data of the National Health Insurance Research Database of Taiwan. PARTICIPANTS: We identified 4160 patients aged 1-30 years with newly diagnosed T1DM and no history of AC at baseline. For each patient with T1DM, four non-T1DM controls (n=16,640) were matched by sex. The mean follow-up time was 6 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Multivariate Cox proportional hazards regression analysis was used to evaluate the risk of AC. We additionally evaluated the association between risk of AC and T1DM progression by examining Diabetes Complications Severity Index (aDCSI) changes from the date of diagnosis until the end of follow-up. RESULTS: The overall incidence of allergic conjunctivitis (AC) was higher in the type 1 diabetes mellitus (T1DM) cohort than in the control cohort (23.0 vs 13.5 per 1000 person-years, adjusted incidence rate ratio (aIRR): 1.59, 95% CI 1.47 to 1.71). Relative to that in patients with mildly progressive T1DM, the risk of AC increased as the adapted Diabetes Complications Severity Index (aDCSI) increased (aIRR: 1.68, 3.78 and 18.8, with yearly changes in aDCSI score: 0.51 to 1.00, 1.01 to 2.00, and >2.00 vs <0.51, respectively; for trend <0.001). CONCLUSION: Patients with T1DM are at an elevated risk of developing AC; this risk increases with T1DM progression. The T helper type 1/T helper type 2 hypothesis is an overly simplistic explanation for this association.

Sitagliptin and risk of heart failure hospitalization in patients with type 2 diabetes on dialysis: A population-based cohort study.

The incidence of heart failure hospitalization (HHF) after taking sitagliptin in type 2 diabetes (T2DM) patients with end stage renal disease (ESRD) on dialysis is unclear. In this population-based cohort study, we identified individuals with T2DM and ESRD on dialysis who were treated with sitagliptin between 2009 and 2011 and randomly selected a control cohort matched by age, sex, duration of T2DM, hypertension medications, use of statin and aspirin, sulfonylureas, glinides, and insulin usage, atherosclerotic heart disease, congestive heart failure and chronic obstructive pulmonary disease at a 1:4 ratio. Multivariable Cox proportional hazards regression analysis was used to evaluate HHF risk. The overall incidence of HHF was higher in the sitagliptin cohort than in the control cohort (1130 vs. 754 per 10000 person-years; adjusted hazard ratio (HR): 1.52, 95% CI = 1.21-1.90). There was a significant trend towards increased HHF risk associated with increased sitagliptin dose (p for trend < 0.01). Subjects at greater risk of HHF after taking sitagliptin were those without severe hypoglycemia, without ACE inhibitors treatment, with history of heart failure or receiving hemodialysis rather than peritoneal dialysis. In conclusion, use of sitagliptin was associated with an increased risk of HHF in patients with T2DM on dialysis.

Asiatic acid and maslinic acid protected heart via anti-glycative and anti-coagulatory activities in diabetic mice.

The cardiac protective effects of asiatic acid (AA) and maslinic acid (MA) in diabetic mice were examined. These triterpenoids at 0.1 or 0.2% of the diet were supplied to diabetic mice for 12 weeks. The AA or MA treatments decreased plasma glucose and HbA1c levels, and creatine phosphokinase and lactate dehydrogenase activities in diabetic mice (p < 0.05). AA or MA intake increased the amount deposited in the heart which retained the cardiac glutathione content and reduced the production of reactive oxygen species, N(ε)-(carboxymethyl)-lysine, pentosidine, methylglyoxal, interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in the hearts of diabetic mice (p < 0.05). AA or MA intake lowered plasma von Willebrand factor and fibrinogen levels, and factor VII activity (p < 0.05), also AA or MA intake maintained circulating antithrombin-III and protein C activities (p < 0.05). AA or MA treatments down-regulated cardiac expression of NADPH oxidase, aldose reductase, nuclear factor kappa B (NF-κB) p65 and p-p38; as well as reserving glyoxalase 1 expression (p < 0.05). These two compounds at only 0.2% lowered cardiac expression of NF-κB p50, p-ERK1/2 and the receptor of the advanced glycation endproduct (p < 0.05). These findings support the conclusion that the supplement of these triterpenoids could protect the heart under diabetic conditions via attenuating glycative injury and coagulatory disorders.

Anti-Diabetic Effects of Madecassic Acid and Rotundic Acid.

Anti-diabetic effects of madecassic acid (MEA) and rotundic acid (RA) were examined. MEA or RA at 0.05% or 0.1% was supplied to diabetic mice for six weeks. The intake of MEA, not RA, dose-dependently lowered plasma glucose level and increased plasma insulin level. MEA, not RA, intake dose-dependently reduced plasminogen activator inhibitor-1 activity and fibrinogen level; as well as restored antithrombin-III and protein C activities in plasma of diabetic mice. MEA or RA intake decreased triglyceride and cholesterol levels in plasma and liver. Histological data agreed that MEA or RA intake lowered hepatic lipid droplets, determined by ORO stain. MEA intake dose-dependently declined reactive oxygen species (ROS) and oxidized glutathione levels, increased glutathione content and maintained the activity of glutathione reductase and catalase in the heart and kidneys of diabetic mice. MEA intake dose-dependently reduced interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels in the heart and kidneys of diabetic mice. RA intake at 0.1% declined cardiac and renal levels of these inflammatory factors. These data indicated that MEA improved glycemic control and hemostatic imbalance, lowered lipid accumulation, and attenuated oxidative and inflammatory stress in diabetic mice. Thus, madecassic acid could be considered as an anti-diabetic agent.