Effects of smoking and smoking cessation on human serum metabolite profile: results from the KORA cohort study

Background: Metabolomics helps to identify links between environmental exposures and intermediate biomarkers of disturbed pathways. We previously reported variations in phosphatidylcholines in male smokers compared with non-smokers in a cross-sectional pilot study with a small sample size, but knowledge of the reversibility of smoking effects on metabolite profiles is limited. Here, we extend our metabolomics study with a large prospective study including female smokers and quitters. Methods: Using targeted metabolomics approach, we quantified 140 metabolite concentrations for 1,241 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) human cohort at two time points: baseline survey conducted between 1999 and 2001 and follow-up after seven years. Metabolite profiles were compared among groups of current smokers, former smokers and never smokers, and were further assessed for their reversibility after smoking cessation. Changes in metabolite concentrations from baseline to the follow-up were investigated in a longitudinal analysis comparing current smokers, never smokers and smoking quitters, who were current smokers at baseline but former smokers by the time of follow-up. In addition, we constructed protein-metabolite networks with smoking-related genes and metabolites. Results: We identified 21 smoking-related metabolites in the baseline investigation (18 in men and six in women, with three overlaps) enriched in amino acid and lipid pathways, which were significantly different between current smokers and never smokers. Moreover, 19 out of the 21 metabolites were found to be reversible in former smokers. In the follow-up study, 13 reversible metabolites in men were measured, of which 10 were confirmed to be reversible in male quitters. Protein-metabolite networks are proposed to explain the consistent reversibility of smoking effects on metabolites. Conclusions: We showed that smoking-related changes in human serum metabolites are reversible after smoking cessation, consistent with the known cardiovascular risk reduction. The metabolites identified may serve as potential biomarkers to evaluate the status of smoking cessation and characterize smoking-related diseases

Association of daily tar and nicotine intake with incident myocardial infarction: Results from the population-based MONICA/KORA Augsburg Cohort Study 1984 - 2002

<p>Abstract</p> <p>Background</p> <p>Cigarette smoking has been shown to be one of the most important risk factors for cardiovascular diseases. However, little is known about cumulative effects of daily tar and nicotine intake on the risk of incident myocardial infarction (MI) so far. To bridge this gap, we conducted an analysis in a large prospective study from Southern Germany investigating associations of daily tar and nicotine intake with an incident MI event.</p> <p>Methods</p> <p>The study was based on 4,099 men and 4,197 women participating in two population-based MONICA Augsburg surveys between 1984 and 1990 and followed up within the KORA framework until 2002. During a mean follow-up of 13.3 years, a number of 307 men and 80 women developed an incident MI event. Relative risks were calculated as hazard ratios (HRs) estimated by Cox proportional hazards models adjusted for cardiovascular risk factors.</p> <p>Results</p> <p>In the present study, male regular smokers consumed on average more cigarettes per day than female regular smokers (20 versus 15) and had a higher tar and nicotine intake per day. In men, the MI risk compared to never-smokers increased with higher tar intake: HRs were 2.24 (95% CI 1.40-3.56) for 1-129 mg/day, 2.12 (95% CI 1.37-3.29) for 130-259 mg/day and 3.01 (95% CI 2.08-4.36) for ≥ 260 mg/day. In women, the corresponding associations were comparable but more pronounced for high tar intake (HR 4.67, 95% CI 1.76-12.40). Similar associations were observed for nicotine intake.</p> <p>Conclusions</p> <p>The present study based on a large population-based sample adds important evidence of cumulative effects of tar and nicotine intake on the risk of incident MI. Even low or medium tar and nicotine intake revealed substantial risk increases as compared to never-smokers. Therefore, reduction of tar and nicotine contents in cigarettes cannot be seen as a suitable public health policy in preventing myocardial infarction.</p

systematic review and meta-analysis of published studies and unpublished individual participant data

Objective To quantify the association between long working hours and alcohol use. Design Systematic review and meta-analysis of published studies and unpublished individual participant data. Data sources A systematic search of PubMed and Embase databases in April 2014 for published studies, supplemented with manual searches. Unpublished individual participant data were obtained from 27 additional studies. Review methods The search strategy was designed to retrieve cross sectional and prospective studies of the association between long working hours and alcohol use. Summary estimates were obtained with random effects meta-analysis. Sources of heterogeneity were examined with meta-regression. Results Cross sectional analysis was based on 61 studies representing 333 693 participants from 14 countries. Prospective analysis was based on 20 studies representing 100 602 participants from nine countries. The pooled maximum adjusted odds ratio for the association between long working hours and alcohol use was 1.11 (95% confidence interval 1.05 to 1.18) in the cross sectional analysis of published and unpublished data. Odds ratio of new onset risky alcohol use was 1.12 (1.04 to 1.20) in the analysis of prospective published and unpublished data. In the 18 studies with individual participant data it was possible to assess the European Union Working Time Directive, which recommends an upper limit of 48 hours a week. Odds ratios of new onset risky alcohol use for those working 49-54 hours and ≥55 hours a week were 1.13 (1.02 to 1.26; adjusted difference in incidence 0.8 percentage points) and 1.12 (1.01 to 1.25; adjusted difference in incidence 0.7 percentage points), respectively, compared with working standard 35-40 hours (incidence of new onset risky alcohol use 6.2%). There was no difference in these associations between men and women or by age or socioeconomic groups, geographical regions, sample type (population based v occupational cohort), prevalence of risky alcohol use in the cohort, or sample attrition rate. Conclusions Individuals whose working hours exceed standard recommendations are more likely to increase their alcohol use to levels that pose a health risk

Mental health in the aged: prevalence, covariates and related neuroendocrine, cardiovascular and inflammatory factors of successful aging

<p>Abstract</p> <p>Background</p> <p>Although aging is accompanied by diminished functioning, many elderly individuals preserve a sense of well-being. While the concept of "successful aging" has been popular for many decades, little is known about its psycho-physiologic and endocrine underpinnings. KORA-Age is a population-based, longitudinal study designed to determine the prevalence of successfully aged men and women between 65 and 94 years old in the MONICA/KORA Augsburg cohort of randomly selected inhabitants. Specifically, we aim to identify predictors of successful aging and to elucidate bio-psychosocial mechanisms that maintain mental health and successful adaptation despite adverse experiences of life and aging.</p> <p>Methods/Design</p> <p>Components of successful aging were assessed in a telephone survey of 4,127 participants (2008-2009) enrolled in the MONICA/KORA cohort, on average, 13 years earlier. Psychosocial, somatic and behavioural predictors are used to determine factors that contribute to successful aging. An age-stratified random sub-sample (n = 1,079) participated in a personal interview where further psychological mechanisms that may underlie successful adaptation (resilience, social support, attachment) were examined. The interactions among neuroendocrine systems in the aging process are investigated by studying the cortisol/dehydroepiandrosterone-sulfate ratio, the level of insulin-like growth factor I, and oxytocin.</p> <p>Discussion</p> <p>Longitudinal determinants of successful aging can be assessed based on a follow-up of an average of 13 years. A comprehensive analysis of biological as well as physio-psychological information provides a unique opportunity to investigate relevant outcomes such as resilience and frailty in the elderly population.</p

Patterns of Multimorbidity in the Aged Population. Results from the KORA-Age Study

Multimorbidity is a common problem in aged populations with a wide range of individual and societal consequences. The objective of the study was to explore patterns of comorbidity and multimorbidity in an elderly population using different analytical approaches. Data were gathered from the population-based KORA-Age project, which included 4,127 persons aged 65–94 years living in the city of Augsburg and its two surrounding counties in Southern Germany. Information on the presence of 13 chronic conditions was collected in a standardized telephone interview and a self-administered questionnaire. Patterns of comorbidity and multimorbidity were analyzed using prevalence figures, logistic regression models and exploratory tetrachoric factor analysis. The prevalence of multimorbidity (≥2 diseases) was 58.6% in the total sample. Hypertension and diabetes (Odds Ratio [OR] 2.95, 99.58% confidence interval [CI] [2.19–3.96]), as well as hypertension and stroke (OR 2.00, 99.58% CI [1.26–3.16]) most often occurred in combination. This association was independent of age, sex and the presence of other conditions. Using factor analysis, we identified four patterns of multimorbidity: the first pattern includes cardiovascular and metabolic diseases, the second includes joint, liver, lung and eye diseases, the third covers mental and neurologic diseases and the fourth pattern includes gastrointestinal diseases and cancer. 44% of the persons were assigned to at least one of the four multimorbidity patterns; 14% could be assigned to both the cardiovascular/metabolic and the joint/liver/lung/eye pattern. Further common pairs were the mental/neurologic pattern combined with the cardiovascular/metabolic pattern (7.2%) or the joint/liver/lung/eye pattern (5.3%), respectively. Our results confirmed the existence of co-occurrence of certain diseases in elderly persons, which is not caused by chance. Some of the identified patterns of multimorbidity and their overlap may indicate common underlying pathological mechanisms

Metabolic Profiling Reveals Distinct Variations Linked to Nicotine Consumption in Humans — First Results from the KORA Study

Exposure to nicotine during smoking causes a multitude of metabolic changes that are poorly understood. We quantified and analyzed 198 metabolites in 283 serum samples from the human cohort KORA (Cooperative Health Research in the Region of Augsburg). Multivariate analysis of metabolic profiles revealed that the group of smokers could be clearly differentiated from the groups of former smokers and non-smokers. Moreover, 23 lipid metabolites were identified as nicotine-dependent biomarkers. The levels of these biomarkers are all up-regulated in smokers compared to those in former and non-smokers, except for three acyl-alkyl-phosphatidylcholines (e.g. plasmalogens). Consistently significant results were further found for the ratios of plasmalogens to diacyl-phosphatidylcolines, which are reduced in smokers and regulated by the enzyme alkylglycerone phosphate synthase (alkyl-DHAP) in both ether lipid and glycerophospholipid pathways. Notably, our metabolite profiles are consistent with the strong down-regulation of the gene for alkyl-DHAP (AGPS) in smokers that has been found in a study analyzing gene expression in human lung tissues. Our data suggest that smoking is associated with plasmalogen-deficiency disorders, caused by reduced or lack of activity of the peroxisomal enzyme alkyl-DHAP. Our findings provide new insight into the pathophysiology of smoking addiction. Activation of the enzyme alkyl-DHAP by small molecules may provide novel routes for therapy

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

AbstractBackgroundThe genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.MethodsWe analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.ResultsThe SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9).ConclusionsThis large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression

Validated inference of smoking habits from blood with a finite DNA methylation marker set

Inferring a person’s smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (