Chih Ching Yeh

Protein carbonyl levels, glutathione S-transferase polymorphisms and risk of colorectal cancer

Oxidative stress has been associated with the carcinogenesis of colorectal cancer. Glutathione S-transferases (GSTs) modulate the elimination of free radical. We conducted a case-control study to examine the interaction between oxidative stress and GSTs polymorphisms on colorectal cancer risk. This study recruited 727 pathologically confirmed colorectal adenocarcinoma cases and 736 sex- and age-matched controls. Plasma protein carbonyls, as a parameter of oxidative stress, were measured using enzyme-linked immunosorbent assay. Genotypes of GSTM1, GSTT1 and GSTP1 genes were determined using polymerase chain reaction methods. The protein carbonyl levels were significantly higher in cases than in controls and exerted a dose-response relationship (P for trend < 0.001). Compared with the first carbonyl quartile subjects, those in the second, third and fourth quartiles had odds ratios (ORs) of 1.54 [95% confidence interval (CI) = 1.13-2.10], 1.52 (95% CI = 1.11-2.07) and 1.98 (95% CI = 1.46-2.67), respectively. This effect was significantly modified by GSTM1 genotype (P for interaction = 0.037). The three-way interaction analysis revealed that interactions between GSTM1 genotype and cigarette smoking and between GSTT1 genotype and alcohol drinking further modified the oxidative stress contribution for colorectal cancer (p for interaction were 0.067 and 0.054, respectively). The impact of oxidative stress was more prominent among ever-smokers with GSTM1-null genotype (OR = 3.45, 95% CI = 1.70-6.97) and ever-drinkers with GSTT1-present genotype (OR = 3.87, 95% CI = 1.82-8.25). Our results indicate that interaction between oxidative stress and GSTs polymorphisms may play an important role in the pathogenesis of colorectal cancer.

Association of Hepatitis C Virus Infection With Risk of ESRD: A Population-Based Study

BACKGROUND The association between chronic hepatitis C virus (HCV) infection and end-stage renal disease (ESRD) has been widely debated. STUDY DESIGN National population-based cohort study. SETTING & PARTICIPANTS Insurance claims data from the Taiwan National Health Insurance Research Database in 2000-2005. PREDICTOR Chronic HCV infection as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification. OUTCOMES ESRD as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULTS We identified 6,291 adults with chronic HCV infection. The control group included 31,455 sex- and age-matched individuals without evidence of chronic hepatitis. The incidence of ESRD was 2.14-fold higher in patients with chronic HCV infection (HR, 1.53; 95% CI, 1.17-2.01; P = 0.002) than in patients without HCV infection. Age stratification analysis showed that patients aged 50-59 years with chronic HCV infection (HR, 7.77; 95% CI, 4.23-14.3; P < 0.001) had the highest risk of developing ESRD relative to patients aged 20-49 years without chronic HCV infection (interaction P < 0.001). LIMITATIONS Lack of clinical data. CONCLUSIONS Patients with chronic HCV infection are at greater risk of developing ESRD than individuals without chronic HCV infection. In addition, the risk of developing ESRD is highest in younger patients with HCV infection. Early renal screening programs should be initiated for this high-risk group of young individuals with chronic HCV infection.

An intron 4 VNTR polymorphism of the endothelial nitric oxide synthase gene is associated with early-onset colorectal cancer

Endothelial‐derived nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), may play an important role in colorectal carcinogenesis. However, the putative contribution of common eNOS genetic polymorphisms to colorectal cancer risk remains unknown. We genotyped 3 polymorphisms of eNOS (T‐786C, G894T, and intron4b/a) in 727 colorectal adenocarcinoma cases and 736 age‐ and sex‐matched healthy controls in Taiwan. Genotypes of the T‐786C and G894T polymorphisms were determined by fluorescence polarization assays and the 27‐bp variable number of tandem repeat (VNTR) polymorphism in intron 4 (intron4b/a) was analyzed by PCR. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Among younger participants (≤60 yrs), the intron4a variant genotype was associated with a significantly increased risk of colorectal cancer, compared with the intron4bb genotype (OR = 1.60, 95% CI = 1.04–2.46). In addition, those young individuals bearing a greater number of high‐risk genotypes (OR > 1, i.e., CT+TT for T‐786C, ba+aa for intron4b/a, and GG for G894T) of eNOS had a higher colorectal cancer risk (ptrend = 0.039). Compared with younger individuals without any putative high‐risk genotypes, those with 3 high‐risk genotypes had a significantly greater cancer risk (OR = 1.89, 95% CI = 1.04–3.43). Our results suggest that the eNOS intron4b/a polymorphism may contribute to early‐onset colorectal cancer risk in the Taiwanese population.

Polymorphisms of cytochrome P450 1A1, cigarette smoking and risk of coronary artery disease

Epidemiological evidence has demonstrated a strong relationship between cigarette smoking and coronary artery disease (CAD). Cytochrome P450 1A1 (CYP1A1) is a key enzyme that metabolizes the cigarette toxin relevant to smoking-induced atherogenesis. This case-control study examined the role of CYP1A1 polymorphisms, CYP1A1 2A (T6235C) and CYP1A1 2C (A4889G), in susceptibility to smoking-related CAD. We recruited 481 patients with 50% or more luminal obstructions in the coronary artery and 228 normal subjects at a medical center in Taiwan. Information on socio-demographic and smoking status was obtained using a self-administered questionnaire. Genotypes of CYP1A1 2A and CYP1A1 2C polymorphisms were determined by polymerase chain reaction or in combination with restriction fragment length polymorphism methods. The results did not show any significant association between CYP1A1 2A polymorphism and CAD risk. However, the CYP1A1 2C G allele was more prevalent in controls (p=0.035) with a dose-response protective effect for CAD. Compared to the A/A genotype, the multivariate logistic regression analysis showed that carrying the CYP1A1 2C G/G genotype was associated with a significantly decreased risk for CAD (OR=0.32, 95% CI=0.15-0.70). The beneficial effect of the CYP1A1 2C G/G genotype was even greater for never smokers than those carrying the A/A genotype (OR=0.23, 95% CI=0.08-0.71). The interaction between genotype and smoking status was not statistically significant. Our findings suggest that the CYP1A1 2C G/G genotype may reduce the risk for CAD in the Taiwanese population and this effect appeared to be more pronounced among never smokers.

GSTM1, GSTT1, GSTP1, and GSTA1 genetic variants are not associated with coronary artery disease in Taiwan

BACKGROUND AND OBJECTIVE The genetic variants of xenobiotic-metabolizing enzymes, such as those encoded by glutathione-S-transferase (GST) genes, may be associated with the risk of coronary artery disease (CAD). To investigate the genetic factors for CAD, we examined the GSTM1, GSTT1, GSTP1, and GSTA1 genotypes in a CAD cohort in Taiwan. METHODS Our study included 458 CAD participants and 209 control participants who received coronary angiography to assess CAD. The severity of CAD was defined as the number of coronary vessels with 50% or greater stenosis. Sequence variation of the GSTM1 and GSTT1 genes was determined using a polymerase chain reaction (PCR). The GSTP1 (Ile105Val), and GSTA1 (-69C>T) genetic variants were identified using a combination of PCR and restriction fragment length polymorphism analysis. Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals. RESULTS Among the GST genetic variants examined, the GSTT1 null genotype was more prevalent in CAD participants with 3 stenosed vessels than in control participants (OR=1.64, P=.02). This association was no longer observed after adjusting for age, sex, smoking, alcohol use, diabetes mellitus, and serum levels of total cholesterol and high-density lipoprotein cholesterol (OR=1.28, P=.40). Both univariate and multivariate logistic regression analyses found no significant associations between CAD and the other genetic variants, either separately or in combination. In addition, no effects of interactions between the genotypes and environmental factors, such as cigarette smoking, were significantly associated with the risk of CAD. CONCLUSION The GST genetic variants examined were not associated with susceptibility to CAD in our Taiwanese cohort. This null association requires further confirmation with larger samples.

Positive Association Between Hepatitis C Infection and Oral Cavity Cancer: A Nationwide Population-Based Cohort Study in Taiwan

Objectives The association between viral hepatitis (B and C) and oral cavity cancer has been widely debated. This nationwide, population-based cohort study assessed the subsequent risk of oral cavity cancer among patients with chronic viral hepatitis infection. Materials and Methods Data were retrieved from insurance claims data of 1,000,000 randomly sampled individuals covered under the Taiwan National Health Insurance system. We identified a total of 21,199 adults with chronic viral hepatitis infection (12,369 with HBV alone, 5,311 with HCV alone, and 3,519 with HBV/HCV dual infections) from 2000–2005. Comparison group comprised 84,796 sex- and age-matched subjects without viral hepatitis during the same study period. Incidence and risk of subsequent oral cavity cancer were measured until 2008. Results The incidence of oral cavity cancers was 2.28-fold higher among patients with HCV alone than non-viral hepatitis group (6.15 versus 2.69 per 10,000 person-years). After adjusting for sociodemographic covariates, HCV alone was significantly associated with an increased risk for oral cavity cancer (hazard ratio (HR) = 1.90, 95% confidence interval (CI) = 1.20–3.02). This positive association was highest among individuals in the 40–49-year age group (HR = 2.57, 95% CI = 1.21–5.46). However, there were no significant associations between HBV alone or HBV/HCV dual infections and risk for oral cavity cancer. Conclusion Our data suggest that HCV but not HBV infection is a risk factor for oral cavity cancer. In addition, subjects with HCV infection tend to be at early onset risk for oral cavity cancer. This finding needs to be replicated in further studies.

Association between chronic viral hepatitis infection and breast cancer risk: a nationwide population-based case-control study.

BackgroundIn Taiwan, there is a high incidence of breast cancer and a high prevalence of viral hepatitis. In this case-control study, we used a population-based insurance dataset to evaluate whether breast cancer in women is associated with chronic viral hepatitis infection.MethodsFrom the claims data, we identified 1,958 patients with newly diagnosed breast cancer during the period 2000-2008. A randomly selected, age-matched cohort of 7,832 subjects without cancer was selected for comparison. Multivariable logistic regression models were constructed to calculate odds ratios of breast cancer associated with viral hepatitis after adjustment for age, residential area, occupation, urbanization, and income. The age-specific (<50 years and ≥50 years) risk of breast cancer was also evaluated.ResultsThere were no significant differences in the prevalence of hepatitis C virus (HCV) infection, hepatitis B virus (HBV), or the prevalence of combined HBC/HBV infection between breast cancer patients and control subjects (p = 0.48). Multivariable logistic regression analysis, however, revealed that age <50 years was associated with a 2-fold greater risk of developing breast cancer (OR = 2.03, 95% CI = 1.23-3.34).ConclusionsHCV infection, but not HBV infection, appears to be associated with early onset risk of breast cancer in areas endemic for HCV and HBV. This finding needs to be replicated in further studies.

Tumor Site- and Stage-Specific Associations between Allelic Variants of Glutathione S-Transferase and DNA-Repair Genes and Overall Survival in Colorectal Cancer Patients Receiving 5-Fluorouracil-Based Chemotherapy

Introduction Our retrospective cohort study investigated the effect of tumor site and stage on the associations between the allelic variants of glutathione S-transferase (GST) and DNA-repair genes and overall survival (OS) in CRC patients treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy. Material and Methods We genotyped GSTM1, GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln in 491 CRC patients between 1995 and 2001. A Cox proportional-hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between the allelic variants and OS. Survival analyses were performed for each allelic variant by using the log-rank test and Kaplan-Meier analysis. Results The CRC patients with the XPD Gln allelic variants had poorer survival than patients with the Lys/Lys genotype (HR  = 1.38, 95% CI  = 1.02–1.87), and rectal cancer patients had the poorest survival among them (HR  = 1.87, 95% CI  = 1.18–2.95). A significantly shorter OS was observed among stage II/III colon cancer patients with the XRCC1 Gln allelic variants (HR  = 1.69, 95% CI  = 1.06–2.71), compared to those with XRCC1 Arg/Arg genotype. In the combined analysis of the XRCC1 and XPD genes patients with stage II/III tumors, the poorest OS occurred in colon cancer patients with the XRCC1 Gln and XPD Gln allelic variants (HR  = 2.60, 95% CI  = 1.19–5.71) and rectal cancer patients with the XRCC1 Arg/Arg and XPD Gln allelic variants (HR  = 2.77, 95% CI  = 1.25–6.17). Conclusion The XPD and XRCC1 allelic variants may be prognostic markers for CRC patients receiving 5-FU based chemotherapy. The contributions of the XPD and XRCC1 allelic variants to OS are tumor site- and/or stage-dependent.

Risk Factors Associated with Colorectal Cancer in a Subset of Patients with Mutations in MLH1 and MSH2 in Taiwan Fulfilling the Amsterdam II Criteria for Lynch Syndrome

Background and Aim Lynch syndrome, caused by germline mutations in mismatch repair genes, is a predisposing factor for colorectal cancer (CRC). This retrospective cohort study investigated the risk factors associated with the development of CRC in patients with MLH1 and MSH2 germline mutations. Methods In total, 301 MLH1 and MSH2 germline mutation carriers were identified from the Amsterdam criteria family registry provided by the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A Cox proportional hazard model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association between the risk factors and CRC development. A robust sandwich covariance estimation model was used to evaluate family dependence. Results Among the total cohort, subjects of the Hakka ethnicity exhibited an increased CRC risk (HR = 1.62, 95% CI = 1.09–2.34); however, those who performed regular physical activity exhibited a decreased CRC risk (HR = 0.62, 95% CI = 0.41–0.88). The CRC risk was enhanced in MLH1 germline mutation carriers, with corresponding HRs of 1.72 (95% CI = 1.16–2.55) and 0.54 (95% CI = 0.34–0.83) among subjects of the Hakka ethnicity and those who performed regular physical activity, respectively. In addition, the total cohort with a manual occupation had a 1.56 times higher CRC risk (95% CI = 1.07–2.27) than did that with a skilled occupation. Moreover, MSH2 germline mutation carriers with blood group type B exhibited an increased risk of CRC development (HR = 2.64, 95% CI = 1.06–6.58) compared with those with blood group type O. Conclusion The present study revealed that Hakka ethnicity, manual occupation, and blood group type B were associated with an increased CRC risk, whereas regular physical activity was associated with a decreased CRC risk in MLH1 and MSH2 germline mutation carriers.

Association of Sjögrens Syndrome in Patients with Chronic Hepatitis Virus Infection: A Population-Based Analysis

Objective The association between Sjögren’s syndrome (SS) and chronic hepatitis virus infection is inconclusive. Hepatitis B (HBV) and hepatitis C virus (HCV) infections are highly prevalent in Taiwan. We used a population-based case-control study to evaluate the associations between SS and HBV and HCV infections. Materials and Methods We identified 9,629 SS patients without other concomitant autoimmune diseases and 38,516 sex- and age-matched controls without SS from the Taiwan National Health Insurance claims data between 2000 and 2011. We utilized multivariate logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between SS and HBV and HCV infections. Sex- and age-specific (<55 and ≥55 years) risks of SS were evaluated. Results The risk of SS was higher in patients with HCV than in those without chronic viral hepatitis (OR = 2.49, 95% CI = 2.16–2.86). Conversely, HBV infection was not associated with SS (OR = 1.10, 95% CI = 0.98–1.24). Younger HCV patients were at a higher risk for SS (<55 years: OR = 3.37, 95% CI = 2.62–4.35; ≥55 years: OR = 2.20, 95% CI = 1.84–2.62). Men with HCV were at a greater risk for SS (women: OR = 2.26, 95% CI = 1.94–2.63; men: OR = 4.22, 95% CI = 2.90–6.16). Only men with chronic HBV exhibited a higher risk of SS (OR = 1.61, 95% CI = 1.21–2.14). Conclusion HCV infection was associated with SS; however, HBV only associated with SS in men.