Variations in the UDP-glucuronosyltransferase 1A1 gene for the development of unconjugated hyperbilirubinemia in Taiwanese.

INTRODUCTION: Results of several studies have indicated that the variation of c.-3279T>G in the UDP-glucuronosyltransferase (UGT)1A1 gene could be a further factor for the development of hyperbilirubinemia. However, this variant has not been reported in the Taiwanese population. MATERIALS & METHODS: PCR-restriction fragment length polymorphism was utilized to determine variants at nucleotides -3279 (*60), -53 (*28) and 211 (*6) in the UGT1A1 gene for 178 Taiwanese hyperbilirubinemic patients and 200 controls. RESULTS: A total of ten and nine diplotypes were observed in the hyperbilirubinemic patients and controls, respectively. Subjects possessing diplotypes of compound haplotypes (*60/*28, *60/*6, *1/*60 plus *1/*28 plus *1/*6); *60/*60; *60/*60 plus 1/*28 and *6/*6 were significantly related to hyperbilirubinemia development, with an odds ratio of 7.83-188.00 (p = 0.012 approximately <0.001). A subgroup possessing diplotypes of *60/*60 plus *28/*28 were only found in hyperbilirubinemic patients, not in the controls. Bilirubin concentration amongst these patients carrying a diplotype of *60/*60 plus *28/*28 (mean [SD]: 39.2 [10.77] micromol/l) was significantly higher than that in the diplotype subgroups of *60/*60 plus *1/*28 (30.4 [4.10] micromol/l) and *6/*6 (30.3 [3.08] micromol/l) (p = 0.046 and 0.034, respectively). CONCLUSIONS: The c.-3279T>G variant is a further factor for the development of hyperbilirubinemia. Our results also demonstrate that possessing the *60/*60 plus *28/*28 diplotype in the UGT1A1 gene is a determinant of relatively higher bilirubin values amongst hyperbilirubinemic patients.

UDP-glucuronosyltransferase 1A7 polymorphisms are associated with liver cirrhosis.

Variations in the UDP-glucuronosyltransferase (UGT) 1A7 gene have been found to be related to the development of hepatocellular carcinoma (HCC). Since the pathogenesis of liver cirrhosis is not dissimilar to that of HCC, we hypothesized that UGT1A7 genetic polymorphisms may be associated with liver cirrhosis. PCR-restriction fragment length polymorphism was utilized to determine UGT for 1A7 genotypes for the 159 patients with liver cirrhosis and 263 gender/age matched controls. Simple logistic regression analysis revealed that significant risk factors for liver cirrhosis were (1) hepatitis B virus (HBV) infection, (2) hepatitis C virus (HCV) infection, (3) HBV infection plus HCV infection and (4) low-activity UGT1A7 genotypes. The results of further multivariate logistic regression confirmed these associations. Interaction of low-activity UGT1A7 genotypes and HBV (or HCV) infection produced an additive effect upon the risk for the development of liver cirrhosis [observed odds ratio (OR) (54.59) greater than the expected OR (18.05)]. UGT1A7 low/low genotype was also related to advanced liver cirrhosis (Child-Pugh classes C and/or B) (OR=7.50, P=0.009). This study demonstrates the novel findings that carriage of low-activity UGT1A7 genotypes represents a risk factor for the development and functional severity of liver cirrhosis.

Inhibition of intermediate-conductance Ca2+-activated K+ channel and cytoprotective properties of 4-piperidinomethyl-2-isopropyl-5-methylphenol.

The ionic mechanisms and cytoprotective activities of 4-piperidinomethyl-2-isopropyl-5-methylphenol (THPI), an analogue of thymol, were investigated in HL-60 granulocytes and in human erythrocytes, respectively. THPI inhibited K+ outward current (I(K)) in a concentration-dependent manner in HL-60 leukocytes, with an IC50 value of 4 microM. Neither iberiotoxin (200 nM) nor paxilline (1 microM) suppressed the amplitude of I(K), whereas clotrimazole (5 microM) significantly inhibited it. In the inside-out configuration of single channel recordings, application of THPI (5 microM) into the bath medium did not alter the single-channel conductance of intermediate-conductance Ca2+-activated K+ (IK(Ca)) channels (i.e K(Ca)3.1 channels), but it suppressed the channel activity significantly. THPI-induced inhibition of IK(Ca) channels was reversed by a further application of 1-ethyl-2-benzimidazolinone (10 microM). THPI-induced reduction in IK(Ca)-channel activity in these cells was primarily due to a decrease in mean open time. These results provide direct evidence that THPI is capable of suppressing the activity of IK(Ca) channels in HL-60 cells. The antioxidant action of THPI also revealed a beneficial cytoprotective effect against mitomycin C-mediated haemolytic effect in human erythrocytes. The results of this study suggest that blockade of IK(Ca) channels and the membrane-protecting activity of THPI would combine to have beneficial effects in lessening the severity of haemolytic crisis and reducing anaemia in sickle cell disease.

Presence of the exoU gene of Pseudomonas aeruginosa is correlated with cytotoxicity in MDCK cells but not with colonization in BALB/c mice.

A total of 141 independent strains of Pseudomonas aeruginosa with different heterogeneities in the exo gene (exoS, exoT, exoU, and exoY) background were examined for their pathogenic roles. Results indicated that the exoU gene is the major contributor to cytotoxicity in Madin-Darby canine kidney cells but is not related to bacterial colonization in mice.

UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma risk and onset age.

OBJECTIVES: It has been demonstrated that the UDP-glucuronosyltransferase (UGT) 1A7*3 allele is a risk factor for hepatocellular carcinoma (HCC) in German and Japanese populations. In this study, therefore, we evaluated the association between UGT1A7 genetic polymorphisms and HCC risk in southern Taiwan, where hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are endemic. METHODS: The 217 HCC patients and 291 controls enrolled in this case-control study were genotyped for UGT1A7 polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Univariate logistic regression analysis revealed that presence of UGT1A7*2 and *3 alleles was associated with HCC risk [odds ratio (OR) = 1.50, 95% confidence interval (CI): 1.04 approximately 2.16 and OR = 1.73, 95% CI: 1.19 approximately 2.52, respectively]. Multiple logistic regression analysis demonstrated that significant independent risk factors for HCC were male gender (OR = 2.53, 95% CI: 1.42 approximately 4.52), HBV infection (OR = 13.73, 95% CI: 8.04 approximately 23.46), HCV infection (OR = 83.93, 95% CI: 37.01 approximately 190.32), and low-activity UGT1A7 genotype [high/low (H/L) genotype: OR = 1.93, 95% CI: 1.12 approximately 3.32; low/low (L/L) genotype: OR = 3.06, 95% CI: 1.50 approximately 6.24]. For male HCC patients, significantly earlier onset age was observed for those bearing the UGT1A7 low-activity genotype as opposed to those with the high-activity analogue (median age: 50 vs 59 yr; p < 0.05). CONCLUSIONS: An inverse dose-response relationship was demonstrated between the detoxifying activity of the UGT1A7 genotypes and HCC. Of the male HCC patients, median onset age for those carrying an UGT1A7 low-activity genotype was 9 yr lower than those bearing the high-activity variant.

Link between colorectal cancer and polymorphisms in the uridine-diphosphoglucuronosyltransferase 1A7 and 1A1 genes.

AIM: To investigate the relationship between single nucleotide polymorphisms in the uridine-diphosphoglucuronosyltransferase (UGT) UGT1A7 and UGT1A1 genes and patients suffering from colorectal cancer (CRC). METHODS: A case-control study was designed in order to investigate the genotypes of the UGT1A7 and UGT1A1 genes, which were identified by the polymerase chain reaction-restriction fragment length polymorphism (RFLP) method, for 268 CRC patients and 441 healthy controls. RESULTS: The results of simple logistical regressions revealed odds ratios (ORs) of 1.97 (P<0.001), 1.91 (P<0.001), and 2.03 (P<0.001) for patients who carried the UGT1A7*1/*3 genotype, UGT1A7*3 allele, and variant-211 UGT1A1 allele. The interaction of UGT1A7*3 allele and variant-211 UGT1A1 allele produced an additive effect on the risk for the development of CRC (observed OR (2.34) greater than expected OR (1.59)). For the 268 patients, the results of simple logistical regressions indicated that the OR of developing metastases was 4.90 (P<0.001) and 4.89 (P<0.001) for the individuals possessing UGT1A7*3 allele and variant-211 UGT1A1 allele, respectively. The results of multivariate logistical regressions confirmed these findings (OR = 2.51, P = 0.01; and OR = 2.71, P = 0.01, respectively). The interaction of these two variants resulted in an additive effect on the risk for metastases amongst patients (observed OR (6.83) greater than expected OR (4.56)). CONCLUSION: In conclusion, carriage of the UGT1A7*3 allele, as well as variant-211 UGT1A1 allele represents a risk factor for the development of, and a determinant for, metastases associated with CRC patients.

Genetic factors related to unconjugated hyperbilirubinemia amongst adults.

Some variations in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are involved in the development of unconjugated hyperbilirubinemia. We hypothesize that other genetic factors may also be associated with this disease. A total of 227 adults with normal routine haematology and liver function (apart from bilirubin testing for which they revealed bilirubin > or = 25.7 micromol/l and unconjugated bilirubin/total bilirubin > or = 80%), and 235 sex- and age-matched controls, were recruited. All subjects were analysed for UGT1A1, glucose-6-phosphate dehydrogenase (G6PD) and organic anion transporter polypeptide 2 (OATP2) genotypes using polymerase chain reaction-restriction fragment length polymorphism. The results indicated that G6PD deficiency, variant UGT1A1 gene and variant OATP2 gene were risk factors for hyperbilirubinemia. The odds ratios (OR) (with 95% confidence interval) were 220.83 (34.68-1406.30), 73.61 (17.01-318.63), 45.15 (11.19-182.22), 15.46 (4.35-54.99) and 6.51 (1.83-23.09), respectively, for individuals featuring the common UGT1A1/OATP2 haplotypes homozygous/heterozygous, compound heterozygous/heterozygous, compound heterozygous/wild-type, heterozygous/heterozygous and heterozygous/wild-type variations amongst subjects with normal G6PD activity. Amongst the subjects with G6PD deficiency, the OR was 159.00 (24.57-1028.94) for individuals carrying variations in both UGT1A1 and OATP2 genes. The UGT1A1/OATP2 haplotypes homozygous/wild-type, homozygous/compound heterozygous and homozygous/homozygous for G6PD normal and variant/wild-type for G6PD deficient individuals were only observed in the case group, and not in the control group. Amongst hyperbilirubinemic adults, bilirubin values tended to parallel variation status of their haplotypes. Adults featuring certain haplotypes in UGT1A1, OATP2 and G6PD genes face a high risk of developing unconjugated hyperbilirubinemia.

Elevated levels of plasma VEGF in patients with dengue hemorrhagic fever.

Vascular endothelial growth factor (VEGF) can be produced by monocytes and endothelial cells. It plays important role in angiogenesis and vascular permeability. The phenomenon of extensive plasma leakage into various serous cavities of the body is a cardinal symptom of dengue hemorrhagic fever (DHF). This study was performed to investigate the role of VEGF in patients with DHF. Plasma samples collected from the 53 dengue fever (DF) patients (including 14 patients with DHF), and 5 additional subjects with non-dengue febrile illness as controls were tested for VEGF levels using commercial enzyme-linked immunosorbent assay (ELISA) kits. The results showed that median plasma levels of VEGF in the patients with DHF (54.6 pg ml(-1)) were significantly higher than those of DF (14.6 pg ml(-1)) and control group (27.1 pg ml(-1)) (P<0.05). In addition, VEGF levels in DF patients were not significantly different from those of control patients with non-dengue febrile illness (P=0.17). Multiple regression analysis was used to analyze the clinical variables independently associated with VEGF levels. The data showed that D-dimer levels were significantly associated with VEGF levels. In this study, plasma VEGF levels in patients with DHF were significantly higher than values from DF patients. The association between increased plasma VEGF levels and increased plasma D-dimer levels in the patients with dengue illness suggests that activation of the fibrinolytic system may play a role in VEGF production in the patients with DF.

Risk factors for severe hyperbilirubinemia in neonates.

The incidence of severe neonatal hyperbilirubinemia is higher in Asians than in whites. A case-control study was designed to investigate the effects of eight known risk factors [breast feeding, ABO incompatibility, premature birth, infection, cephalohematoma, asphyxia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene] and a suspicious analog [organic anion transporter 2 (OATP 2) gene] on severe hyperbilirubinemia in Taiwanese neonates. The 72 study subjects and 100 hospital control subjects consisted of neonates with peak serum bilirubin levels > or =342 microM and <256.5 microM, respectively. The PCR-restriction fragment length polymorphism method was applied to detect the UGT1A1, OATP 2, and G6PD genes. The results of multivariate logistic regressions, adjusted for covariates, revealed odds ratios (ORs) of 4.64 [95% confidence interval (CI): 2.25-9.57; p < 0.001], 3.36 (95% CI: 1.54-7.35; p=0.002), and 3.02 (95% CI: 1.30-6.99; p=0.010) for neonates who were fed with breast milk, and carry the variant UGT1A1 gene at nucleotide 211 and the variant OATP 2 gene at nucleotide 388, respectively. The ORs, adjusted for covariates, for the other six risk factors were not statistically significant. The ORs in neonates who had one, two, and three significant risk factors were 8.46 (95% CI: 2.75-34.48; p < 0.001), 22.0 (95% CI: 5.50-88.0; p < 0.001), and 88.0 (95% CI: 12.50-642.50; p < 0.001), respectively. In conclusion, neonates who carry the 211 and 388 variants in the UGT1A1 and OATP 2 genes, respectively, as well as feed with breast milk are at high risk to develop severe hyperbilirubinemia.

Lifestyle and psychosocial factors associated with chronic periodontitis in Taiwanese adults.

BACKGROUND: The development of chronic periodontitis (CP) is a multifactorial process and variation in severity cannot be explained by just a few risk factors. The aims of this study were: 1) to explore the lifestyle and psychosocial factors of CP patients and 2) to estimate the proportion of total CP cases attributable to one or more risk factors considered. METHODS: A case-control study of 250 cases of CP patients and 250 controls were matched by age (within 3 years) and gender. Complete dental examinations were performed based on the clinical criteria for CP for both groups. Structured questionnaires were conducted to collect lifestyle and psychosocial factors. Multivariate logistic regression was applied to assess the association between risk factors and chronic periodontitis. RESULTS: Conditional multivariable logistic regression analysis showed that toothbrushing frequency (odds ratio [OR]: 5.77, if rarely; OR: 3.50, if once a day), mental illness (OR: 5.32, if Chinese Health Questionnaire scores were > or = 6), and smoking (OR: 3.93, if pack years smoked was > 21) are significantly and independently associated with chronic periodontitis. In addition, all these variables reflected a dose-response effect (P trend = <0.001, 0.004, and 0.005, respectively). CONCLUSIONS: For Taiwanese adults, 36.10% of CP cases were presumably attributable to toothbrushing frequency, mental illness, and smoking. These three factors should be the first priorities in establishing a preventive program to improve the periodontal health status.