A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease

Background

Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).

Methods and results

We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification.

Conclusions

In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.     

The association between psychosocial characteristics at work and problem drinking: a cross-sectional study of men in three Eastern European urban populations

Background: Psychosocial factors at work are thought to influence health partly through health behaviours. Aims: To examine the association between effort-reward imbalance and job control and several alcohol related measures in three eastern European populations. Methods: A cross-sectional study was conducted in Novosibirsk (Russia), Krakow (Poland), and Karvina (Czech Republic). The participants completed a questionnaire that included effort-reward at work, job control, and a number of sociodemographic variables. Annual alcohol intake, annual number of drinking sessions, the mean dose of alcohol per drinking session, and binge drinking (⩾80 g of ethanol in one session at least once a week) were based on graduated frequencies in the questionnaire. Data were also available on problem drinking (⩾2 positive answers on CAGE questionnaire) and negative social consequences of drinking. All male participants in full employment (n = 694) were included in the present analyses. Results: After controlling for age and centre, all indices of alcohol consumption and problem drinking were associated with the effort-reward ratio. Adjustment for material deprivation did not change the results but adjustment for depressive symptoms reduced the estimated effects. Job control was not associated with any of the alcohol related outcomes. Conclusions: The imbalance of effort-reward at work is associated with increased alcohol intake and problem drinking. The association appears to be partly mediated by depressive symptoms, which might be either an antecedent or a consequence of men''s drinking behaviour.     

Short to long term mortality of patients hospitalised with heart failure in the Czech Republic--a report from the EuroHeart Failure Survey

BACKGROUND AND AIM: The European Society of Cardiology initiated the EuroHeart Failure Survey to obtain more data about the quality of care in patients hospitalised with suspected heart failure (HF). The Czech Republic was 1 of the 24 European Society countries included in the survey. The aim of this report is to extend the original follow-up period of 12 weeks out to 4 years to assess mortality. METHODS: All admitted patients were screened according to the EuroHeart Survey Protocol, over a 6-week period in six hospitals in Pilsen, Prague and Brno in the year 2000. Annual mortality and cause of death were obtained from the Prague Institute for Health Statistical Information (UZIS Praha). RESULTS: A total of 2365 patients were screened and about 25% of all admitted patients fulfilled the criteria for HF. About 14% of patients died between admission and the 12-week follow-up, 36% of male and 42% of female patients died during the 4-year follow-up (2000-2003). Cardiovascular diseases were the main causes of death (92%). Deceased patients were significantly older, had lower haemoglobin and total plasma cholesterol level, and had renal insufficiency and higher levels of big endothelin and BNP than the survivors. Mortality risk was increased independently by positive history of previous myocardial infarction OR=2.39 (1.59-3.59), by age OR=1.03 (1.01-1.05) and by plasma creatinine level OR=1.04 (1.01-1.07). Treatment with diuretics and digoxin was associated with a higher risk of death; by contrast, a protective effect of beta-blockers and statins was found in these HF patients. CONCLUSION: Patients with HF were older and had a poor prognosis; approximately one third of the patients will die within 3 years.     

Conservativism of the matrix protein of paramyxoviruses

Cross reactions among paramyxoviruses were determined by the immunoblot method. Human parainfluenza viruses, types 1-3, avian parainfluenza virus type 4, mumps, Sendai, and measles viruses were used. Antisera to human parainfluenza viruses were shown to cross-interact with proteins NP and M of other types, and all antisera to the members of Paramyxovirus genus cross-reacted with M proteins of other paramyxoviruses. No cross reactions with measles virus proteins were observed. It is concluded that M protein is the most conservative protein of paramyxoviruses.     

Systemic inflammation in patients with COPD and pulmonary hypertension

STUDY OBJECTIVES: COPD is a systemic disorder that is associated with increases of inflammatory proteins in systemic circulation. However, no data on the potential role of systemic inflammation in pulmonary hypertension secondary to COPD are available. Therefore, our aim was to investigate the degree of systemic inflammation reflected by circulatory levels of C-reactive protein (CRP), tumor-necrosis factor (TNF)-alpha, and interleukin (IL)-6 in COPD patients with and without pulmonary hypertension. DESIGN: Cross-sectional study. SETTING: University hospital, tertiary referral setting. PATIENTS AND MEASUREMENTS: In 43 consecutive patients with COPD (mean [+/- SD] age, 65.0 +/- 10.5 years; mean FEV(1), 46.2 +/- 18.1% predicted), lung function was assessed using body plethysmography; pulmonary artery pressure (Ppa) levels were measured by echocardiography. Serum TNF-alpha and IL-6 levels were assessed by enzyme-linked immunosorbent assay, and high-sensitivity serum CRP levels were measured by chemiluminescent immunoassay. RESULTS: Pulmonary hypertension was present in 19 patients and was absent in 24 patients. In patients with pulmonary hypertension, serum CRP and TNF-alpha levels were significantly higher than in those patients without hypertension (median, 3.6 mg/L [25th to 75th percentile, 1.4 to 13.0 mg/L] vs 1.8 mg/L [25th to 75th percentile, 0.8 to 2.8 mg/L; p = 0.034]; and median, 4.2 pg/mL [25th to 75th percentile, 3.4 to 10.9 pg/mL] vs 3.1 pg/mL [25th to 75th percentile, 2.1 to 4.2 pg/mL]; p = 0.042, respectively). No differences were seen in serum IL-6 (median, 10.4 pg/mL [25th to 75th percentile, 8.8 to 12.2 pg/mL] vs 10.5 pg/mL [25th to 75th percentile, 9.4 to 39.1 pg/mL]; p = 0.651) between the groups. In multiple linear regression analysis, the following two variables were independent predictors of systolic Ppa (R(2) = 0.373): Pao(2) (p = 0.011); and log-transformed serum CRP level (p = 0.044). CONCLUSION: We conclude that increases in Ppa in patients with COPD are associated with higher serum levels of CRP and TNF-alpha, raising the possibility of a pathogenetic role for low-grade systemic inflammation in the pathogenesis of pulmonary hypertension in COPD patients.     

Glutathione S-transferase and microsomal epoxide hydrolase gene polymorphisms and risk of chronic obstructive pulmonary disease in Slovak population

Aim

To determine the risk of chronic obstructive pulmonary disease (COPD) associated with polymorphisms in the glutathione S-transferase (GST) M1, GST T1, and microsomal epoxide hydrolase (EPHX1) genes in a cohort of Slovak population.

Methods

Two hundred and seventeen patients with the diagnosis of COPD and 160 control subjects were enrolled in the study. Blood samples were collected from all subjects and the DNA from peripheral blood lymphocytes was used for subsequent genotyping assays, using polymerase chain reaction and restriction fragment-length polymorphism methods.

Results

In an unadjusted model, an increased risk for COPD was observed in subjects with EPHX1 His113-His113 genotype (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.20-4.69; P = 0.008), compared with the carriers of the Tyr113 allele. However, after the adjustments for age, sex, and smoking status, the risk was not significant (adjusted OR, 1.79; 95% CI, 0.91-3.53; P = 0.093). In a combined analysis of gene polymorphisms, the genotype combination EPHX1 His113-His113/GSTM1 null significantly increased the risk of COPD in both, unadjusted (OR, 5.08; 95% CI, 1.70-20.43; P = 0.001) and adjusted model (OR, 4.87; 95% CI, 1.57-15.13; P = 0.006).

Conclusion

Although none of the tested gene polymorphisms was significantly related to an increased risk of COPD alone, our results suggest that the homozygous exon 3 mutant variant of EPHX1 gene in the combination with GSTM1 null genotype is a significant predictor of increased susceptibility to COPD in the Slovak population. The findings of the present study emphasize the importance of detoxifying and antioxidant pathways in the pathogenesis of COPD.Chronic obstructive pulmonary disease (COPD) represents a major public health care problem worldwide due to its increasing prevalence, morbidity, and mortality (1). Generally, COPD is characterized by progressive and only partially reversible airflow limitation (2). Although cigarette smoking is the most important risk factor for COPD, only 20%-30% of chronic smokers develop severe impairment of lung function associated with COPD (3). Besides smoking, other environmental and genetic factors and gene-environment interactions influence the development of COPD (4).Severe α-1-antitrypsin deficiency is a well established genetic risk factor for COPD that has provided a basis for the protease-antiprotease hypothesis in the pathogenesis of COPD (5,6). Other candidate genes that might play a role in the development of COPD are involved in endogenous protease/antiprotease imbalance, inflammatory processes, metabolism of mutagens and carcinogens in tobacco smoke, and in mucocilliary clearance (7). Interindividual differences in the polymorphisms of enzymes metabolizing the xenobiotic substances and free radicals contained in the cigarette smoke may play a role in the individual susceptibility to the decrease in lung functions in smokers (8).Microsomal epoxide hydrolase (EPHX1) is generally considered to be a protective enzyme involved in the defense from oxidative damage (9,10). Two common polymorphic sites in the EPHX1 gene that influence the enzyme activity can be detected (11). An exon 3 thymine-to-cytosine mutation changes Tyr residue 113 to His, thus reducing the enzyme activity by about 50%. The second mutation, an adenine-to-guanine transition in exon 4 of the gene, changes His residue 139 to Arg and results in the production of EPHX1 with the activity increased by about 25% (11). The combination of these polymorphisms leads to a formation of several functional phenotypes of EPHX1. The slow metabolizing type of EPHX1 was associated with emphysema and COPD (9). In another study, an association of slow metabolizing EPHX1 phenotype with an accelerated deterioration of lung function in smokers was observed (12). In addition, several studies conducted in different populations have suggested that the EPHX1 genotype may influence individual susceptibility to COPD (9,13-15). Nevertheless, other investigators failed to confirm an association between the EPHX1 gene polymorphisms and COPD (16-18).Glutathione S-transferases (GST) play a role in the detoxification of carcinogenic compounds contained in cigarette smoke and in the antioxidant protection (19,20). Recently, the GSTM1 and the GSTT1 gene polymorphisms have been excessively studied with respect to their potential contribution to the risk of COPD (8,17,21,22). The deficiency in the activity of GSTM1 and GSTT1 enzymes is caused by the inherited homozygous absence of the GSTM1 or GSTT1 gene, respectively (ie, GSTM1 null or GSTT1 null genotype). Previously, the homozygous GSTM1 null genotype has been associated with lung cancer (23), emphysema (21), and reductions in the lung function in Caucasian smokers with non-small-cell lung cancer (22). However, another study conducted in Koreans found no differences in the frequencies of polymorphic genotypes of GSTM1 and GSTT1 genes between patients with COPD and healthy smokers (17).Since current data on the potential associations between an increased COPD risk and genes encoding the enzymes metabolizing xenobiotic substances are inconsistent, the aim of our study was to analyze the relation between COPD and gene polymorphisms of EPHX1, GSTM1, and GSTT1 genes in a sample of Slovak population.