PTEN polymorphisms and the risk of esophageal carcinoma and gastric cardiac carcinoma in a high incidence region of China

SUMMARY. PTEN, as a tumor suppressor gene, plays an important role in regulating cell growth, proliferation, and apoptosis. Two common polymorphisms, –9C/G and IVS4 (?/+), may alter susceptibility to the disease. To test the hypothesis that the genetic variations of PTEN play a role in the etiology of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA), a population‐based case‐control study was conducted in 350 ESCC patients, 257 GCA patients, and 634 healthy controls from a high‐incidence region of Hebei province, China. The PTEN polymorphisms were genotyped by polymerase chain reaction‐restriction fragment length polymorphism analysis (PCR‐RFLP). The results showed that the family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing ESCC and GCA (the age, gender and smoking status adjusted OR = 1.73 and 1.67; 95% CI = 1.29–2.32 and 1.28–2.19, respectively). The overall distribution of the PTEN –9C/G genotype was not significantly different between cancer patients and controls. Compared with the PTEN IVS4‐/? genotype, the IVS4+/+ genotype significantly decreased the risk of ESCC and GCA development, the adjusted OR was 0.64 (95% CI = 0.44–0.94) and 0.63 (95% CI = 0.41–0.98), respectively. Stratification analysis by gender, age, smoking status and family history of UGIC showed that the PTEN IVS4?/+ genotype only reduced the risk of ESCC (adjusted OR = 0.55, 95%CI = 0.34–0.90) among subjects with family history of UGIC. While the IVS4+/+ genotype decreased the susceptibility to both ESCC and GCA (adjusted OR = 0.61 and 0.57, 95% CI = 0.37–0.98 and 0.34–0.98, respectively) among male subjects, the IVS4+/+ genotype only decreased the risk of ESCC development among subjects younger than 55 years (adjusted OR = 0.43, 95% CI = 0.21–0.85). In addition, the haplotype analysis found that the –9C/IVS4– haplotype increased the risk of developing ESCC and GCA (OR = 1.31 and 1.24, 95% CI = 1.08–1.58 and 1.001–1.53). Our results suggested that the PTEN IVS4+/+ homozygote may play a protective role in the development of ESCC and GCA, while the haplotype –9C/IVS4– might be the risk factor of the development of ESCC and GCA in the high incidence region population of Hebei province, China.     

Increased incidence of infectious diseases during prospective follow-up of human T-lymphotropic virus type II- and I-infected blood donors. Retrovirus Epidemiology Donor Study.

BACKGROUND: To determine whether human T-lymphotropic virus type II (HTLV-II) infection is associated with an increased incidence of bacterial infections, we prospectively observed cohorts of HTLV-I- and HTLV-II-infected and seronegative subjects in 5 US cities. METHODS: Of 1340 present and former blood donors examined at enrollment, 1213 (90.5%) were re-examined after approximately 2 years, including 136 HTLV-I- and 337 HTLV-II-seropositive subjects and 740 demographically stratified HTLV-seronegative subjects. All subjects were seronegative for human immunodeficiency virus. Odds ratios (ORs) for incident disease outcomes were adjusted for covariates, including age, sex, race or ethnicity, education, and, if significantly associated with the outcome, blood center, donation type, income, smoking, alcohol intake, and injected drug use. RESULTS: Compared with seronegative status, HTLV-II infection was associated with an increased incidence of bronchitis (OR, 1.81; 95% confidence interval [CI], 1.20-2.75), bladder and/or kidney infection (OR, 1.94; 95% CI, 1.26-2.98), oral herpes infection (OR, 9.54; 95% CI, 3.33-27.32), and a borderline increased incidence of pneumonia (OR, 2.09; 95% CI, 0.92-4.76); HTLV-I infection was associated with an increased incidence of bladder and/or kidney infection (OR, 2.79; 95% CI, 1.63-4.79). One incident case of HTLV-I-positive adult T-cell leukemia was observed (incidence, 348 per 100,000 HTLV-I person-years), and 1 case of HTLV-II-positive tropical spastic paraparesis-HTLV-associated myelopathy was diagnosed (incidence, 140 per 100,000 HTLV-II person-years). CONCLUSIONS: These data support an increased incidence of infectious diseases among otherwise healthy HTLV-II- and HTLV-I-infected subjects. They are also consistent with the lymphoproliferative effects of HTLV-I, and with neuropathic effects of HTLV-I and HTLV-II.     

Smoking and alanine aminotransferase levels in hepatitis C virus infection: implications for prevention of hepatitis C virus progression

BACKGROUND: Alcohol consumption is a well-known risk factor for elevated ALT levels, but the role of cigarette smoking is unclear. METHODS: We collected a cross-sectional sample of 6095 inhabitants 35 years or older in a community with hyperendemic hepatitis B and C virus infections. We assayed levels of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and anti-hepatitis C virus antibody (anti-HCV). Multivariate logistic regression was performed to determine the factors for elevated ALT levels (> or =40 U/L) among people with different hepatitis infection statuses. RESULTS: Prevalence of elevated ALT levels in individuals who were seronegative for both infections or seropositive for HBsAg or anti-HCV was 3.9%, 11.1%, and 30.8%, respectively. Subjects with elevated ALT levels were more likely to be seropositive for anti-HCV, male, and seropositive for HBsAg; to drink alcohol; to smoke; and to have undergone blood transfusion (P<.05). An association was found between elevated ALT levels and the consumption of cigarettes and alcohol among anti-HCV-seropositive subjects. In multivariate logistic analyses, alcohol consumption (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2-4.1) and smoking (OR, 1.8; 95% CI, 1.1-2.7) were significantly associated with elevated ALT levels among anti-HCV-seropositive subjects, but no such association was found among HBsAg-seropositive subjects. The odds of elevated ALT levels were 7 times higher (95% CI, 2.7-18.8) for the anti-HCV-seropositive patients who smoked 1 or more packs of cigarettes per day and frequently drank alcohol than for those who did not. CONCLUSIONS: Smoking and alcohol consumption are independently associated with elevated ALT levels among anti-HCV-seropositive individuals but not among HBsAg-seropositive individuals. Patients who are seropositive for anti-HCV are strongly advised not to smoke and drink alcohol to reduce the possible risk for aggravating the liver dysfunction.     

Association of Helicobacter pylori infection with esophageal adenocarcinoma and squamous cell carcinoma: a meta‐analysis

To evaluate the relationship of Helicobacter pylori and cytotoxin‐associated gene A (CagA) positive strains with esophageal neoplasm, including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), the authors conducted a meta‐analysis using a predefined protocol. PubMed, Web of Science, China biology medical literature database, Wanfang, and China National Knowledge Infrastructure were searched for relevant articles from the first available year to April 8, 2013. The fixed or random effect pooled measure was selected based on heterogeneity among studies, which was evaluated using Q test and the I² of Higgins and Thompson. Metaregression was used to explore the sources of between‐study heterogeneity. Publication bias was analyzed by Begg's funnel plot and Egger's regression test. The association was assessed by odds ratio (OR) with 95% confidence interval (CI). A total of 28 eligible studies were included in the meta‐analysis. There was a significant inverse association between H. pylori infection (pooled OR, 0.57; 95% CI, 0.44–0.73) and EAC; CagA‐positive H. pylori strains were less likely to be associated with EAC compared with CagA‐negative strains (pooled OR, 0.64; 95% CI, 0.52–0.79). However, there was no statistically significant association between H. pylori/CagA‐positive H. pylori strains infection and ESCC, and the pooled ORs were 1.16 (95% CI, 0.83–1.60) and 0.97 (95% CI, 0.79–1.19). But significant associations between CagA‐positive H. pylori strains infection and ESCC risk were found in the stratified analysis of the study location (Asian and non‐Asian), and the summary ORs were 0.74 (95% CI, 0.57–0.97) and 1.41 (95% CI, 1.02–1.94). H. pylori infection and CagA‐positive strains are associated with decreased risk of EAC in the overall population. No significant association was found between H. pylori infection/CagA‐positive strains and ESCC. But CagA‐positive strains might have a positive association with ESCC in non‐Asian population and an inverse association in Asian population.     

Factors associated with the presence of multiple Lugol‐voiding lesions in patients with esophageal squamous‐cell carcinoma

Multicentric squamous dysplasia of the esophagus is characterized by multiple Lugol‐voiding lesions (LVLs) on Lugol chromoendoscopy. Multiple LVLs are associated with a very high risk of multiple cancers arising in the esophagus as well as the head and neck. To gain insight into the pathogenesis of multiple LVLs of the esophageal mucosa, we studied risk factors for the development of such lesions in 76 patients who had a current or previous diagnosis of esophageal squamous cell carcinoma. All patients underwent Lugol chromoendoscopy of the esophageal mucosa. The history of tobacco and alcohol use was documented. Polymorphisms of the aldehyde dehydrogenase type 2 (ALDH2) gene were identified by polymerase chain reaction using sequence‐specific primers. Clinical factors related to multiple LVLs were analyzed. All patients with multiple LVLs were drinkers. On univariate analysis, male sex (odds ratio [OR] 15, 95% confidence interval [CI] 1.84–122.45: P = 0.011), presence of the ALDH2‐2 allele (OR 4.5, 95% CI 1.55–13.24: P = 0.006), and smoking index ≥1000 (OR 2.6, 95% CI 1.02–6.6: P = 0.045) were associated with multiple LVLs. On multivariate analysis, male sex (OR 10.02, 95% CI 1.13–88.44: P = 0.038) and presence of the ALDH2‐2 allele (OR 4.56, 95% CI 1.4–14.82: P = 0.012) were associated with multiple LVLs. Among drinkers, a daily alcohol intake of ≥100 g pure ethanol with the ALDH2‐2 allele (OR 17.5, 95% CI 1.97–155.59: P = 0.01) and a daily alcohol intake of <100 g pure ethanol with the ALDH2‐2 allele (OR 8.85, 95% CI 1.68–46.69: P = 0.01) more strongly correlated with multiple LVLs than did a daily alcohol intake of <100 g pure ethanol without the ALDH2‐2 allele, whereas a daily alcohol intake of ≥100 g pure ethanol without the ALDH2‐2 allele (OR 4.0, 95% CI 0.54–29.81: P = 0.18) did not. In conclusion, male sex and the ALDH2‐2 allele are associated with an increased risk for multiple LVLs of the esophageal mucosa in patients with esophageal squamous cell carcinoma. Among drinkers with the ALDH2‐2 allele, the risk of multiple LVLs increased in parallel to the daily alcohol intake.     

Ad36 adipogenic adenovirus in human non‐alcoholic fatty liver disease

Aims: Infection with specific pathogens may lead to increased adiposity. The human adenovirus 36 (Ad36) is a relatively new factor in promoting adipogenesis. It seems to improve the metabolic profile, expanding adipose tissue and enhancing insulin sensitivity in animal models. The aim of this study was to investigate whether any association or predictor effect of Ad36 seropositivity is present in non‐alcoholic fatty liver disease (NAFLD), a condition associated with obesity and insulin resistance (IR). Methods: Sixty‐five NAFLD patients and 114 controls were investigated. Ultrasound bright liver score (BLS), body composition, IR evaluated by homeostasis model assessment of insulin resistance index (HOMA or HOMA‐IR) and serum neutralization assay for antibodies to Ad36 were assessed. Results: Ad36‐seropositive patients have a lower risk of bright liver [OR 0.505 (95% confidence interval (CI) 0.265–0.962)]; greater IR leads to a higher risk of bright liver [OR 9.673 (95% CI 4.443–21.058)]. Among NAFLD, Ad36‐seropositive vs. Ad36‐seronegative patients did not show a significant IR difference. Ad36‐seropositive NAFLD patients, with the same levels of HOMA and BLS, had greater body mass index and body fat mass, in comparison with seronegative NAFLD patients. By a multiple linear regression model, BLS was explained by HOMA (β 0.513; P<0.0001), high density lipoprotein cholesterol (β?0.219, P<0.006) and Ad36 seropositivity (β?0.202, P<0.005); Ad36 seropositivity did not explain HOMA in the other multiple logistic regression model. Conclusions: Ad36 seropositivity is not associated with a significant difference of IR in NAFLD patients, but is associated with a greater adiposity. Ad36 seropositivity is associated with a lower occurrence of NAFLD and bright liver, which, conceivably, is not directly mediated by IR.     

Assessment of factors associated with smoking cessation at diagnosis or during follow‐up of Crohn's disease

Background and Aim

Smoking cessation is known to improve the course of Crohn's disease (CD). However, the factors associated with smoking cessation after CD diagnosis have not been well established.

Methods

Clinical characteristics and change in smoking status were evaluated in 445 current smokers at the time of CD diagnosis. Patients were classified into three subgroups based on their final smoking status and time of smoking cessation: non‐quitters, quitters at diagnosis, and quitters during follow‐up.

Results

The overall smoking cessation rate was 55.7% (248 of 445 patients). The diagnosis of CD was the main reason for quitting (41.5%, 103 of 248 patients). Smoking cessation at the time of CD diagnosis was associated with intestinal resection within 3 months from CD diagnosis (odds ratio [OR] 2.355, 95% confidence interval [CI] 1.348–4.116, P = 0.003), light smoking (OR 2.041, 95% CI 1.157–3.602, P = 0.014), and initiation of smoking before 18 years of age (OR 0.570, 95% CI 0.327–0.994, P = 0.047). Light smoking (OR 1.762, 95% CI 1.019–3.144, P = 0.043) and initiation of smoking before 18 years (OR 0.588, 95% CI 0.381–0.908, P = 0.017) were also associated with overall smoking cessation.

Conclusion

Quitters after CD diagnosis, including quitters at diagnosis and quitters during follow‐up, had features distinct from those of non‐quitters. Given the motivation at CD diagnosis, a detailed history of smoking habits should be taken and all current smokers should be encouraged to quit smoking at the time of CD diagnosis.     

Association between positive murine double minute 2 expression and clinicopathological characteristics of esophageal squamous cell carcinoma: a meta‐analysis

The correlations of murine double minute 2 (MDM2) T309G and esophageal cancer were elucidated because the association between MDM2 expression states and clinicopathological parameters of esophageal squamous cell carcinoma (ESCC) is controversial. We conducted a meta‐analysis on studies screened from PubMed, Web of Science, Embase, the Cochrane Library, and the Chinese Biomedical Literature Databases that were published before October 2014. All studies describing the association between MDM2 and ESCC were traced. Meta‐analysis was performed using the STATA software (Stata Corp., College Station, TX, USA). A total of 9 studies with 707 cases and 324 controls were included. MDM2 expression was higher in ESCC than in normal esophageal epithelium (odds ratio [OR] 10.38, 95% confidence interval [CI] 6.42–16.78, P < 0.001). High MDM2 expression was associated with early primary tumor stage (T1/T2 vs. T3/T4, OR 0.59, 95% CI 0.38–0.92, P = 0.018) and increased risk of regional lymph node metastasis (N0 vs. N1, OR 1.66, 95% CI 1.03–2.67, P = 0.039). However, no relationship was observed between MDM2 expression and the risk of distant metastasis (OR = 2.09, 95% CI 1.00–4.36, P = 0.050), and MDM2 was not significantly correlated with TP53 expression (OR 1.22, 95% CI 0.53–2.77, P = 0.643). Our analysis suggests that MDM2 acts as a potent marker of early primary tumor stage but higher risk of regional lymph node metastasis in ESCC. However, because of the limited number of studies included, the result should be further clarified by well‐designed prospective studies.     

Smoking increases the risk of coronary artery disease in Chinese with Chlamydia pneumoniae infection

BACKGROUND: The infection with Chlamydia pneumoniae (Cp) has been claimed to associate with coronary artery disease (CAD). However, the seroepidemiological study of association between Cp infection and CAD still remains a source of controversy. The aim of the present study is to investigate the possible association of Cp infection with CAD in Chinese mainland population and the potential role of Cp infection combined with the traditional risk factors in CAD. METHODS: 1422 hospitalized patients with angiographically demonstrated CAD and 297 controls were recruited and tested for specific Cp IgG with enzyme-linked immunoassay (ELISA). RESULTS: The prevalence of Cp IgG seropositivity in patients with CAD was significantly higher than that in controls (31.1% vs. 24.9%, P=0.035). Unadjusted odds ratios (OR) and 95% confidence intervals (CI) for CAD with the presence of seropositivity of IgG to Cp was 1.4 (1.0-1.8). After full adjustment for possible confounders on multiple logistic regression analysis, only a weak association of Cp infection with CAD was found. The adjusted OR (95% CI) for CAD associated with Cp infection was 1.3 (0.95-1.71, P=0.1). To further delineate the potential role of Cp infection in CAD, we divided subjects into seropositive (n=516) and seronegative (n=1203) groups according to their Cp IgG status. Notably, the adjusted OR (95% CI) for CAD associated with smoking was 4.0 (1.8-8.6) in the seropositive group, 0.9 (0.5-1.4) in the seronegative group, indicating that smoking can significantly increase the risk of CAD in subjects with Cp infection. CONCLUSIONS: Cp infection is not strongly associated with CAD in Chinese mainland population; however, smoking increases the risk of CAD in those with Cp infection.     

Meta‐analysis of alcohol consumption and risk of extrahepatic bile system cancer

Aim: Alcohol consumption increases the risk of liver cancer. However, there is still controversy regarding alcohol consumption and the risk of extrahepatic bile system cancer (EBSC). We performed a meta‐analysis to provide an overview of the relevant studies and gain more robust estimates of the relationship between alcohol consumption and risk of EBSC. Methods: Relevant studies published between January 1966 and October 2010 were identified by searching Medline, Embase and the Cochrane Library. Studies were selected using a priori defined criteria. The strength of the relationship between alcohol consumption and risk of EBSC was assessed by adjusted odds ratio (OR). Results: A total of 113 767 participants from 10 studies (nine case–control studies and one cohort study) were identified in this meta‐analysis. The studies provided adjusted overall OR estimates for drinkers versus non‐/low drinkers, leading to a pooled adjusted OR of 0.82 (95% confidence interval [CI] = 0.72–0.94, P for heterogeneity = 0.194, I² = 27.2%). The overall adjusted OR of hospital‐based studies and population‐based studies were 0.80 (95% CI = 0.65–0.99, P = 0.260) and 0.79 (95% CI = 0.64–0.98, P = 0.119), respectively. For the heavy drinkers, the adjusted OR significance increased to 1.58 (95% CI = 0.97–2.57, P for heterogeneity = 0.055, I² = 65.4%), but it had no statistical significance. Conclusion: There is evidence that moderate alcohol consumption lowers the risk of EBSC compared with non‐/low alcohol consumption, but not heavy alcohol consumption. Further multicenter and better controlled studies are required to confirm these findings.     

A gene–environment interaction between smoking and shared epitope genes in HLA–DR provides a high risk of seropositive rheumatoid arthritis

Objective

The main genetic risk factor for rheumatoid arthritis (RA) is the shared epitope (SE) of HLA–DR, while smoking is an important environmental risk factor. We studied a potential gene–environment interaction between SE genes and smoking in the etiology of the 2 major subgroups of RA: rheumatoid factor (RF)–seropositive and RF‐seronegative disease.

Methods

A population‐based case–control study involving incident cases of RF‐seropositive and RF‐seronegative RA (858 cases and 1,048 controls) was performed in Sweden. Cases and controls were classified according to their cigarette smoking status and HLA–DRB1 genotypes. The relative risk of developing RA was calculated for different gene/smoking combinations and was compared with the relative risk in never smokers without SE genes.

Results

The relative risk of RF‐seropositive RA was 2.8 (95% confidence interval [95% CI] 1.6–4.8) in never smokers with SE genes, 2.4 (95% CI 1.3–4.6) in current smokers without SE genes, and 7.5 (95% CI 4.2–13.1) in current smokers with SE genes. Smokers carrying double SE genes displayed a relative risk of RF‐seropositive RA of 15.7 (95% CI 7.2–34.2). The interaction between smoking and SE genes was significant, as measured by the attributable proportion due to interaction, which was 0.4 (95% CI 0.2–0.7) for smoking and any SE, and 0.6 (95% CI 0.4–0.9) for smoking and a double SE. Neither smoking nor SE genes nor the combination of these factors increased the risk of developing RF‐seronegative RA.

Conclusion

The disease risk of RF‐seropositive RA associated with one of the classic genetic risk factors for immune‐mediated diseases (the SE of HLA–DR) is strongly influenced by the presence of an environmental factor (smoking) in the population at risk.

     

Pseudomonas aeruginosa bacteremia over a 10-year period: multidrug resistance and outcomes in transplant recipients

Abstract: Aim. Transplant recipients are at risk for hospital‐acquired infections (HAIs), including those caused by Pseudomonas aeruginosa. Of all HAIs, bloodstream infection (BSI) remains one of the most life‐threatening. Methods. Over a 10‐year period, we studied 503 patients, including 149 transplant recipients, with pseudomonal BSI from the University of Pittsburgh Medical Center. Trends in antimicrobial susceptibility, risk factors for multidrug resistance (MDR), and outcomes were compared between transplant and non‐transplant patients. Results. Resistance to all antibiotic classes was significantly greater in pseudomonal blood culture isolates from transplant compared with non‐transplant patients (P<0.001). Of isolates from transplant recipients (n=207), 43% were MDR, compared with 18% of isolates from non‐transplant patients (n=391) (odds ratio [OR] 3.47; 95% confidence interval [CI] 2.34–5.14, P<0.001). Among all patients, independent risk factors for MDR P. aeruginosa BSI included previous transplantation (OR 2.38; 95% CI 1.51–3.76, P<0.001), hospital‐acquired BSI (OR 2.41; 95% CI 1.39–4.18, P=0.002), and prior intensive care unit (ICU) admission (OR 2.04; 95% CI 1.15–3.63, P=0.015). Mortality among transplant recipients was 42%, compared with 32% in non‐transplant patients (OR 1.55; 95% CI 0.87–2.76, P=0.108). For transplant recipients, onset of BSI in the ICU was the only independent predictor of mortality (OR 8.00; 95% CI 1.71–37.42, P=0.008). Conclusions. Transplant recipients are at greater risk of MDR P. aeruginosa BSI, with an appreciable mortality. Future management must concentrate on the implementation of effective preventative strategies.     

Effects of interferon therapy on development of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis: A meta-analysis of randomized controlled trials

Aim: The role of interferon (IFN) therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)‐related cirrhosis remains controversial. This meta‐analysis aimed to determine whether IFN therapy reduced the incidence of HCC in HCV‐related cirrhotic patients. Methods: We performed a meta‐analysis including eight randomized controlled trials (RCT) (a total of 1505 patients) to assess the effect of IFN therapy on prevention of HCC in patients with HCV‐related cirrhosis. The pooled odds ratios (OR) were calculated using a random or fixed effects model. Results: Our results showed that IFN therapy significantly decreased the overall HCC incidence in HCV‐related cirrhotic patients (OR, 0.29; 95% confidence interval [CI], 0.10–0.80; P = 0.02). HCC risk in patients who failed to achieve sustained virological response (SVR) in the initial IFN‐based treatment was also reduced by maintenance IFN therapy (OR, 0.54; 95% CI, 0.32–0.90; P = 0.02). Subgroup analysis indicated that IFN therapy decreased HCC incidence in HCV‐related cirrhotic patients during long‐term follow up (>48 months) evidently (OR, 0.25; 95% CI, 0.09–0.67; P = 0.006). However, subgroup analysis of four RCT with short‐term follow up (≤48 months) did not demonstrate the significant difference in HCC incidence between IFN‐treated cirrhotic patients and controls (OR, 0.78; 95% CI, 0.39–1.55; P = 0.48). Conclusion: The present study suggested that IFN therapy could efficiently reduce HCC development in patients with HCV‐related cirrhosis; this effect was more evident in the subgroup of patients with long‐term follow up (>48 months). Patients who received maintenance IFN therapy had a lower risk of HCC than controls.     

Early-onset depressive disorders predict the use of addictive substances in adolescence: a prospective study of adolescent Finnish twins

Aims To explore the developmental relationships between early‐onset depressive disorders and later use of addictive substances. Design, setting and participants A sample of 1545 adolescent twins was drawn from a prospective, longitudinal study of Finnish adolescent twins with baseline assessments at age 14 years and follow‐up at age 17.5 years. Measurements At baseline, DSM‐IV diagnoses were assessed with a professionally administered adolescent version of Semi‐Structured Assessment for Genetics of Alcoholism (C‐SSAGA‐A). At follow‐up, substance use outcomes were assessed via self‐reported questionnaire. Findings Early‐onset depressive disorders predicted daily smoking [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.49–3.50, P < 0.001], smokeless tobacco use (OR = 2.00, 95% CI 1.32–3.04, P = 0.001), frequent illicit drug use (OR = 4.71, 95% CI 1.95–11.37, P = 0.001), frequent alcohol use (OR = 2.02, 95% CI 1.04–3.92, P = 0.037) and recurrent intoxication (OR = 1.83, 95% CI 1.18–2.85, P = 0.007) 3 years later. ORs remained significant after adjustment for comorbidity and exclusion of baseline users. In within‐family analysis of depression‐discordant co‐twins (analyses that control for shared genetic and familial background factors), early‐onset depressive disorders at age 14 predicted significantly frequent use of smokeless tobacco and alcohol at age 17.5. Conclusions Our results suggest important predictive associations between early‐onset depressive disorders and addictive substance use, and these associations appear to be independent of shared familial influences.     

Human papillomavirus type 16 infection may be involved in esophageal squamous cell carcinoma carcinogenesis in Chinese Kazakh patients

The aim of this study was to investigate human papillomavirus type 16 (HPV16) prevalence in esophageal squamous cell carcinoma (ESCC) in Xinjiang Kazakh patients and its role in ESCC carcinogenesis. One hundred and fifty cases of ESCC and 150 cases of corresponding normal esophageal mucosa (CNGM) samples were collected from north Xinjiang where the Kazakh ethnic group has lived since ancient times. HPV16 infection in ESCC and CNGM was detected by genotype‐specific polymerase chain reaction. HPV16 DNA was detected in 55 of 150 ESCC samples (36.7%) and 24 of 150 corresponding normal esophageal mucosa samples (16%) with significant differences (P < 0.001, odds ratio = 3.039, 95% confidence interval: 1.756–5.260). No statistically significant correlations were found between HPV16 infection and the age or gender of patients, tumor site, tumor cell differentiation, or lymph node metastasis (P > 0.05). HPV16 infection is common in cases of ESCC in the Kazakh ethnic group in Xinjiang and may be involved in ESCC carcinogenesis.     

Role of epoxide hydrolase 1 gene polymorphisms in esophageal cancer in a high‐risk area in India

Background and Aim: Microsomal epoxide hydrolase 1 (EPHX1) is involved in the metabolism of environmental and tobacco carcinogens. Tobacco smoking, betel quid chewing, and alcohol consumption are the major known risk factors for esophageal cancer. The present case‐control study evaluated the influence of EPHX1 genetic variations on esophageal cancer susceptibility in 142 patients and 185 healthy controls from a high‐incidence region of India where tobacco use and alcohol consumption are widespread and the users of these two substances are also betel quid chewers. Methods: EPHX1 polymorphic alleles (exon 3, Tyr113His and exon 4, His139Arg) were genotyped by polymerase chain reaction–restriction fragment length polymorphism method and direct sequencing. The results were analyzed using logistic regression to calculate odds ratios (OR) and confidence intervals (CI). Results: Patients with exon 4 genotypes (139His/Arg, 139Arg/Arg) and the 139Arg allele were significantly associated with a risk of esophageal cancer (OR_His139Arg 1.887, 95% CI = 1.112–3.201, P = 0.019; OR_Arg139Arg 7.140, 95% CI = 1.276–393.953, P = 0.025 and OR_Arg 1.83, 95% CI = 1.19–2.82, P = 0.003). The 139His/Arg genotype was a significant risk factor for esophageal cancer in tobacco chewers and betel quid chewers. Patients with the 139Arg/Arg genotype were at significantly higher risk for developing a well‐differentiated and moderately‐differentiated grade of tumor. In contrast, the 113His/His genotype of exon 3 was a significant protective factor for esophageal cancer in tobacco smokers (OR 0.291, 95% CI = 0.138–0.616, P = 0.001), betel quid chewers (OR 0.434, 95% CI = 0.236–0.797, P = 0.007), and alcohol users. Conclusion: EPHX1 exon 4 139His/Arg, and 139Arg/Arg genotypes were associated with a higher risk of esophageal cancer in a high‐risk area of India.     

Risk of pancreatic cancer in chronic hepatitis B virus infection: data from the REVEAL‐HBV cohort study

Background and aims: The relationship between the hepatitis B virus (HBV) and pancreatic cancer remains unclear. Because HBV has been isolated from pancreatic tissue, we hypothesized that HBV may play a role in the development of pancreatic carcinoma. Methods: This cohort was recruited between 1991 and 1992. Serum samples obtained at enrolment were tested for HBsAg and HBeAg by radioimmunoassay. Pancreatic cancer diagnosis was ascertained through data linkage with profiles of the National Cancer Registry and Death Certification System in Taiwan from 1 January 1991 to 31 December 2007. Multivariate‐adjusted hazards ratios (HR_adj) with 95% confidence intervals (CI) were derived using Cox proportional hazards models. Results: In total 22 471 subjects were followed up for 342 186 person‐years and 48 had pancreatic cancer. Chronic carriers of HBsAg had a significantly increased risk of pancreatic cancer showing an HR_adj (95% CI) of 1.95 (1.01–3.78). This association was most striking in females, individuals ≤50 years, non‐smokers and non‐drinkers. The HR_adj (95% CI) of developing pancreatic cancer was 5.73 (1.73–19.05) for HBeAg‐seropositive carriers and 1.64 (0.79–3.42) for HBeAg‐seronegative carriers compared with HBsAg‐seronegative non‐carriers. An increased risk of pancreatic cancer was observed for HBsAg‐seropositives with HBV DNA ≥300 copies/ml (HR_adj, 2.44; 95% CI, 1.20–4.95), but not for HBsAg‐seropositives with HBV DNA <300 copies/ml (HR_adj, 0.64; 95% CI, 0.09–4.67). Conclusions: In addition to the well‐established risk of hepatocellular carcinoma, chronic HBV infection may be associated with an increased risk of pancreatic cancer.     

Interaction of alcohol intake and cofactors on the risk of cirrhosis

Objective: Evaluation of the interaction between alcohol intake and cofactors [hepatitis B virus (HBV), hepatitis C virus (HCV), body mass index] and coffee consumption on the risk of cirrhosis. Design: Seven hundred and forty‐nine consecutive patients with chronic liver disease referring to units for liver or alcohol diseases in Italy during a 6‐months period. Teetotalers were excluded. The odds ratios (OR) for cirrhosis were evaluated using chronic hepatitis cases as the control group. Results: An alcohol intake of more than 3 units/day resulted associated with the likelihood of cirrhosis both in males (OR 4.3; 95% CI=2.5–7.3) and in females (OR 5.7; 95% CI=2.3–14.5). A multiplicative interaction on the risk of cirrhosis between risky alcohol intake and HBsAg or HCV‐Ab/HCV‐RNA positivity was observed. A reduction of cirrhosis risk was observed in subjects consuming more than 3 alcohol units/day with increasing coffee intake. The OR for the association with cirrhosis decreased from 2.3 (95% CI=1.2–4.4) in subjects drinking 0–2 cups of coffee/day to 1.4 (95% CI=0.6–3.6) in those drinking more than 2 cups/day. Conclusions: In subjects with an alcohol intake >3 units/day the coexistence of HBV or HCV multiplies the risk of cirrhosis. Coffee represents a modulator of alcoholic cirrhosis risk.     

Association of genetic polymorphisms in PTEN and additional gene–gene interaction with risk of esophageal squamous cell carcinoma in Chinese Han population

This study aims to investigate the association of five single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homologue (PTEN) gene and additional role of gene–gene interaction with esophageal squamous cell carcinoma (ESCC), based on a Chinese case–control study. A total of 871 subjects (420 males and 451 females) were selected, including 425 ESCC cases and 446 controls. Five SNPs were selected for genotyping in the case–control study: rs2735343, rs555895, rs2299939, rs17431184 and rs701848. Logistic regression model was used to examine the association between five SNP and ESCC, and additional interaction among five SNP, odds ratio (OR) and 95% confident interval (95%CI) were calculated. All genotypes were distributed according to Hardy–Weinberg equilibrium in controls. The carriers of homozygous mutant of rs2735343 and rs701848 polymorphism revealed increased ESCC risk than those with wild‐type homozygotes, and OR (95%CI) were 1.27 (1.09–2.08) and 1.45 (1.17–1.98), respectively. We also found a potential gene–gene interaction between rs2735343 and rs701848 (P = 0.0010), and a potential gene–gene interaction among all five SNP (P = 0.0107) after covariates adjustment. Subjects with TC or CC of rs2735343 and TC or CC of rs701848 genotype have highest ESCC risk, compared to subjects with TT of rs2735343 and TT of rs701848 genotype, OR (95% CI) was 2.76 (1.37–3.45) after covariates adjustment. The carriers of homozygous mutant of rs2735343 and rs701848 polymorphism revealed increased ESCC risk. We also found a potential gene–gene interaction between rs2735343 and rs701848 and a potential gene–gene interaction among all five SNPs.     

Genotypes of CYP1A1, SULT1A1 and SULT1A2 and risk of squamous cell carcinoma of esophagus: outcome of a case–control study from Kashmir,India

Studies on associations of various polymorphism in xenobiotic metabolizing genes with different cancers including esophageal squamous cell carcinoma (ESCC) are mixed and inconclusive. To evaluate the association of CYP1A1*4, SULT1A1*2 and SULT1A2*2 genotypes with ESCC risk and their modifying effects on different risk factors of ESCC, we conducted a case–control study in Kashmir, India, an area with relative high incidence of ESCC. We recruited 404 histopathologically confirmed ESCC cases, and equal number of controls, individually matched for sex, age and district of residence to respective case. Information was obtained on various dietary, lifestyle and environmental factors in face‐to‐face interviews, using a structured questionnaire, from each subject. Genotypes were analyzed by polymerase chain reaction, restriction fragment length polymorphism and direct sequencing. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A higher risk was observed in the subjects who harbored variant genotype of CYP1A1*4 (OR = 2.06; 95% CI: 1.28–3.32); and the risk was further enhanced in ever smokers (OR = 3.47; 95% CI: 1.62–7.42), adobe dwellers (OR = 6.71; 95% CI: 3.02–14.89), and biomass fuel users (OR = 5.11; 95% CI: 1.34–19.50). We did not find any significant differences in the polymorphic variants of SULT1A1*2 and SULT1A2*2 between cases and controls. The study indicates that, unlike SULT1A1*2 and SULT1A2*2, the polymorphism of CYP1A1*4 is associated with ESCC risk. However, replicative studies with larger sample size are needed to substantiate our findings.