Modeling stochastic gene expression: From Markov to non-Markov models.

Gene expression is an inherently noisy process due to low copy numbers of mRNA or protein. The involved reaction events may happen in a Markov fashion but also in a non-Markov manner, depending on waiting-time distributions for the occurrence of reaction events. In recent years, many mechanistic models of stochastic gene expression have been developed to forecast fluctuations in mRNA or protein levels. Here we discus commonalities between these models as well as their extensions from Markov to non-Markov models, focusing on the contributions of noisy sources to the protein level. We derive a useful formula for the protein noise quantified by the ratio of the variance over the squared mean. This formula, expressed in terms of the frequencies of the probabilistic events, can be used in the fast evaluation of fluctuations in the protein abundance. Although the detail of the formula may vary from gene to gene, it highlights sources of the protein noise, which can be decomposed into two parts: spontaneous fluctuations resulting from the birth and death of the protein and forced fluctuations originated from switching between the promoter states.

Aromatase (CYP19) promoter gene polymorphism and risk of nonviral hepatitis-related hepatocellular carcinoma.

BACKGROUND: Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6. METHODS: First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case-control studies: 1 in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County. RESULTS: Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (P(trend) = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18-4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele. CONCLUSIONS: This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis-related HCC.

Epidemiological analysis of primary liver cancer in the early 21st century in Guangxi province of China.

BACKGROUND AND OBJECTIVE: In Guangxi province, from 1970s to 1990s, the mortality of primary liver cancer (PLC) ranked the first among a variety of malignant tumors. Investigating the epidemiological characteristics of PLC is very important for developing reasonable and effective treatment strategy, allocating health resources rationally, and evaluating the quality of PLC prevention and control. This study was to analyze the mortality and epidemiological characteristics of PLC in Guangxi province between 2004 and 2005. METHODS: Multi stage stratified cluster random sampling method was used to select 9 counties (cities or urban areas) as sample points. The residents' death causes between 2004 and 2005 were analyzed, and the epidemiological characteristics of PLC were investigated. RESULTS: In the period of 2004-2005, the crude mortality of PLC was 34.39/100,000 in Guangxi province population (55.30/100,000 in men and 13.21/100,000 in women). The national population standardized mortality in 1964 was 22.17/100,000. The man to woman ratio of mortality was 4.19:1. PLC ranked as the first death cause among a variety of malignant tumors, and PLC related death accounted for 30.70% of all tumor related death cases. Age specific mortality of PLC was increased with age, rising significantly from 30 year old (from 25 year old in men and from 40 year old in women), and reached a peak at 75 year old. CONCLUSIONS: The mortality of PLC shows a decreasing trend in Guangxi province in the early 21st century, and the starting age of PLC death peak postpones about 10 years than that in 1990s. It shows that the comprehensive prevention and control measures of PLC implemented in Guangxi province are fruitful. However, the PLC mortality in Guangxi province is still significantly higher than the national average level, and it still ranks as the first death cause in a variety of malignant tumors in Guangxi province. PLC mainly occurs in middle aged and elderly people. The prevention and treatment research of PLC still has a long way to go.

[Study on the relationship between familial clustering of hepatocellular carcinoma and polymorphism of cytochrome P450 2E1 gene in Zhuang population, Guangxi].

OBJECTIVE: To study the relationship between familial clustering of hepatocellular carcinoma (HCC) and the polymorphism of cytochrome P450 2El gene (CYP2E1) as well as of other relevant risk factors to the cancer. METHODS: Peripheral blood samples were collected from 91 members of 10 HCC clustering families and 102 of 10 control families, among Zhuang population, in Guangxi. The area had been with high incidence rate of HCC. Genotypes and allele frequencies of CYP2E1 Rsa I site were determined by polymerase chain reaction, combined with restriction fragment length polymorphism method (PCR-RFLP). Serum HBsAg was tested by means of ELISA. Data on relevant risk factors of the cancer were collected as well, through a unique questionnaire. RESULTS: Frequencies of c1/c1 and c1/c2 genetypes of CYP2E1 Rsa I site were 63.7% and 36.3%, respectively, in the members of families with cancer clustering phenomena. In the members of the control families, these two rates were 48.0% and 52.0%, respectively (OR = 1.901, 95% CI: 1.067-3.387). Difference of genotypes frequencies of CYP2E1 Rsa I site between the members in these two groups was statistically significant (chi2 = 4.797, P = 0.029). According to the results from non-condition logistic regression analysis, the major risk factors on familial clustering of HCC could be listed as: intake of corns, HBsAg carrying status and CYP2E1 c1/c1 genotype. CONCLUSION: The relationship seemed to exist between familial clustering of HCC and the frequencies of polymorphism of cytochrome P450 2E1 gene (CYP2E1). The frequencies of CYP2E1 Rsa I site were neither the only nor the major factor, causing the familial clustering phenomenon of cancer. More possible, it was the affect of syntheses with the involvement of multiple factors.

[A cross-sectional study on liver diseases in the rural residents in southern Guangxi, China].

OBJECTIVE: To study the epidemiological characteristics of liver diseases in a rural population in Southern Guangxi, China. METHODS: The enzyme immunoassays was used to detect of HBsAg and AFP. AFP positive serum samples were further examined for concentration of AFP by using a radio immunoassays. Liver morphological changes were measured with ultrasonography of type B. RESULTS: The positive rates of HBsAg in the studied population was 17.8% (2800/15,701). The prevalence rates of viral hepatitis B, cirrhosis, primary liver cancer, clonorchiasis, fatty liver disease, alcoholic liver disease were 1.1% (173/15,701), 0.4% (63/15,701), 299.3 per 100,000 (47/15,701), 6.6% (1036/15,701), 4.8% (754/15,701) and 0.3% (47/15,701), respectively. The positive rates of HBsAg and the prevalence rates of viral hepatitis B, cirrhosis, primary liver cancer, clonorchiasis, fatty liver disease in male were significantly higher as compared with those in female (5.98 < or = chi(2) < or = 394.78, P < 0.01). No difference was observed in the prevalence rates of liver cavernous hemangioma and hepatic cysts between male and female. The prevalence rates of intrahepatic bile duct stones was significantly higher in female than in male (chi(2) = 30.80, P < 0.01). The positive rates of HBsAg and the prevalence rates of viral hepatitis B and clonorchiasis were decreased with age. But the prevalence rates of cirrhosis, primary liver cancer, fatty liver disease, alcoholic liver disease, liver cavernous hemangioma, hepatic cysts and intrahepatic bile duct stones were increased with age. CONCLUSION: The rural areas in the southern Guangxi are high prevalence regions of liver illness, and the male resident are even at high risk.

Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma.

UNLABELLED: Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) are known to play a role in DNA methylation, synthesis, and repair. The genetic mutations in MTHFR and TYMS genes may have influences on their respective enzyme activities. Data on the association studies of the MTHFR and TYMS genetic polymorphisms and risk of hepatocellular carcinoma (HCC) are sparse. MTHFR and TYMS genotypes were determined on 365 HCC cases and 457 healthy control subjects among Hispanic and non-Hispanic whites and African-Americans in Los Angeles County, California, and among Chinese in the city of Nanning, Guangxi, China. Relative to the high-activity genotype, each low-activity genotype of MTHFR was associated with a statistically nonsignificant 30% to 50% reduction in risk of HCC. Relative to the TYMS3'UTR +6/+6 genotype, individuals with 1 or 2 copies of the deletion allele had a statistically significant 50% reduction in risk of HCC. When we examined HCC risk by the total number of mutant alleles in the 3 polymorphic loci of MTHFR/TYMS (range, 0-4), there was a monotonic decrease in risk with increasing number of mutant alleles (P for trend = 0.003). Individuals possessing the maximum number of mutant alleles (i.e., 4) had an odds ratio of 0.46 (95% confidence interval = 0.23-0.93) for HCC compared with those with no or only 1 mutant allele. CONCLUSION: This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC.

Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine.

Modulation of urinary excretion of green tea polyphenols (GTPs) and oxidative DNA damage biomarker, 8-hydroxydeoxyguanosine (8-OHdG), were assessed in urine samples collected from a randomized, double-blinded and placebo-controlled phase IIa chemoprevention trial with GTP in 124 individuals. These individuals were sero-positive for both HBsAg and aflatoxin-albumin adducts, and took GTP capsules daily at doses of 500 mg, 1000 mg or a placebo for 3 months. Twenty-four hour urine samples were collected before the intervention and at the first and third month of the study. Urinary excretion of 8-OHdG and GTP components was measured by HPLC-CoulArray electrochemical detection. The baseline levels of 8-OHdG and GTP components among the three groups showed homogeneity (P > 0.70), and a non-significant fluctuation was observed in the placebo group over the 3 months (P > 0.30). In GTP-treated groups, epigallocatechin (EGC) and epicatechin (EC) levels displayed significant and dose-dependent increases in both the 500 mg group and 1000 mg group (P < 0.05). The 8-OHdG levels did not differ between the three groups at the 1 month collection, with medians of 1.83, 2.08 and 1.86 ng/mg-creatinine for placebo, 500 and 1000 mg group, respectively (P = 0.999). At the end of the 3 months' intervention, 8-OHdG levels decreased significantly in both GTP-treated groups, with medians of 2.02, 1.03 and 1.15 ng/mg-creatinine for placebo, 500 mg and 1000 mg group, respectively (P = 0.007). These results suggest that urinary excretions of EGC and EC can serve as practical biomarkers for green tea consumption in human populations. The results also suggest that chemoprevention with GTP is effective in diminishing oxidative DNA damage.

Effect of cytokine genotypes on the hepatitis B virus-hepatocellular carcinoma association.

BACKGROUND: In Southern Guangxi, China, chronic infection with the hepatitis B virus (HBV) acquired during the perinatal period from carrier mothers is a primary cause of hepatocellular carcinoma. However, only a minority of HBV carriers eventually develop hepatocellular carcinoma. The authors hypothesized that cytokine genotypes may be important codeterminants of the risk of HBV-related hepatocellular carcinoma. METHODS: The authors examined the correlation between polymorphisms in T-helper 1 (Th1) and Th2 cytokine genes among a group of 250 patients with incident hepatocellular carcinoma (cases) and a group of 250 hospital controls who were matched individually to the index case by age, gender, ethnicity, residence, and month of hospital admission in the city of Nanning, Guangxi, China. RESULTS: Relative to the putative high-activity genotypes, each individual low-activity genotype of interferon gamma, interleukin 12 (IL12), and IL18 was associated with a statistically nonsignificant increase (40-60%) in the risk of hepatocellular carcinoma. This risk increased with increasing numbers of low-activity Th1 genotypes after adjusting for potential confounders (2-sided P value for trend=0.04). Conversely, individual Th2 (IL4, IL10) low-activity genotypes were associated with a statistically nonsignificant reduced risk of hepatocellular carcinoma. This risk decreased with increasing number of low-activity Th2 genotypes after adjusting for potential confounders (2-sided P value for trend=0.01). Individuals who had the maximum number (i.e., 3) of low-activity Th1 genes and the minimum number (i.e., 0) of low-activity Th2 genes showed a relative risk of 20.0 (95% confidence interval, 1.7-235.0). CONCLUSIONS: Diminished cell-mediated immune response, which is controlled genetically, appeared to be an important risk determinant of HBV-related hepatocellular carcinogenesis.