Large rare copy number variants (CNVs) have been recognized as significant genetic risk factors for the development of schizophrenia (SCZ). However, due to their low frequency (1∶150 to 1∶1000) among patients, large sample sizes are needed to detect an association between specific CNVs and SCZ. So far, the majority of genome-wide CNV analyses have focused on reporting only CNVs that reached a significant P-value within the study cohort and merely confirmed the frequency of already-established risk-carrying CNVs. As a result, CNVs with a very low frequency that might be relevant for SCZ susceptibility are lost for secondary analyses. In this study, we provide a concise collection of high-quality CNVs in a large German sample consisting of 1,637 patients with SCZ or schizoaffective disorder and 1,627 controls. All individuals were genotyped on Illumina's BeadChips and putative CNVs were identified using QuantiSNP and PennCNV. Only those CNVs that were detected by both programs and spanned ≥30 consecutive SNPs were included in the data collection and downstream analyses (2,366 CNVs, 0.73 CNVs per individual). The genome-wide analysis did not reveal a specific association between a previously unknown CNV and SCZ. However, the group of CNVs previously reported to be associated with SCZ was more frequent in our patients than in the controls. The publication of our dataset will serve as a unique, easily accessible, high-quality CNV data collection for other research groups. The dataset could be useful for the identification of new disease-relevant CNVs that are currently overlooked due to their very low frequency and lack of power for their detection in individual studies.
To analyse gender differences in the relationship of individual social class, employment status and neighbourhood unemployment rate with present type 2 diabetes mellitus (T2DM).
Five cross-sectional studies.
Studies were conducted in five regions of Germany from 1997 to 2006.
The sample consisted of 8871 individuals residing in 226 neighbourhoods from five urban regions.
Primary and secondary outcome measures
We found significant multiplicative interactions between gender and the individual variables–—social class and employment status. Social class was statistically significantly associated with T2DM in men and women, whereby this association was stronger in women (lower vs higher social class: OR 2.68 (95% CIs 1.66 to 4.34)) than men (lower vs higher social class: OR 1.78 (95% CI 1.22 to 2.58)). Significant associations of employment status and T2DM were only found in women (unemployed vs employed: OR 1.73 (95% CI 1.02 to 2.92); retired vs employed: OR 1.77 (95% CI 1.10 to 2.84); others vs employed: OR 1.64 (95% CI 1.01 to 2.67)). Neighbourhood unemployment rate was associated with T2DM in men (high vs low tertile: OR 1.52 (95% CI 1.18 to 1.96)). Between-study and between-neighbourhood variations in T2DM prevalence were more pronounced in women. The considered covariates helped to explain statistically the variation in T2DM prevalence among men, but not among women.
Social class was inversely associated with T2DM in both men and women, whereby the association was more pronounced in women. Employment status only affected T2DM in women. Neighbourhood unemployment rate is an important predictor of T2DM in men, but not in women.
Epidemiology; Public Health
The objective of this study was to determine the risk for the development of high depressive symptoms in study participants with diagnosed and previously undetected diabetes mellitus compared to those without diabetes in a prospective population-based cohort study in Germany.
We estimated the 5-year cumulative incidence of high depressive symptoms in participants without high depressive symptoms at baseline (n = 3,633, 51.4% men, mean age (SD) 59.1 (7.6) years, 7.0% diagnosed diabetes, 5.3% previously undetected diabetes) from the population-based Heinz Nixdorf Recall study. Diabetes was assessed by self-report, medication, and blood glucose. High depressive symptoms were assessed using CES-D. We calculated odds ratios and their corresponding 95% confidence interval, using multiple logistic regression analyses.
Cumulative 5-year incidences (95% CI) of high depressive symptoms in participants with diagnosed, undetected, and without diabetes were 7.1 (4.2–10.9), 4.1 (1.8–8.0), and 6.5 (5.6–7.4), respectively. The age-sex-adjusted OR for developing high depressive symptoms was 1.22 (0.74–2.03) in participants with diagnosed compared to those without diabetes, and 1.00 (0.59–1.68) after adjustment for BMI, physical activity, education, stroke, and myocardial infarction. The age-sex adjusted OR for developing high depressive symptoms in participants with previously undetected diabetes compared to those without diabetes was 0.72; 0.35–1.48; and fully adjusted 0.62; 0.30–1.30.
We found no significant associations, maybe due to low power. However, our results are in line with a recent meta-analysis suggesting that risk of developing high depressive symptoms in patients with diagnosed diabetes may be moderately higher than in those without diabetes, and that comorbidity may explain in part this association. In participants with previously undetected diabetes, this first longitudinal study indicates that the risk is not increased or may even be decreased. These results support the hypothesis that high depressive symptoms develop due to diabetes-related burden and comorbidity and not due to hyperglycemia or hyperinsulinaemia.
Atherosclerosis is the primary cause of coronary heart disease (CHD), preceding the onset of cardiovascular disease by decades in most cases. Here we examine the association between single nucleotide polymorphisms (SNPs) integrated on Metabochip and coronary artery calcification (CAC), a valid risk factor for CHD, in an unselected, population-based German cohort.
The Metabochip is a custom iSELECT array containing >195,000 SNPs that was designed to support large-scale follow-up of putative associations for metabolic and cardiovascular-associated traits. We used generalized linear regression models to explore the impact of Metabochip SNPs on quantitative CAC in 4,329 participants.
The 9p21 variant, rs1537373, was most strongly associated (Beta = 0.30; 95% confidence interval (CI) = 0.21-0.39; p = 4.05x10-11) with quantitative CAC. The second strongest association with CAC was with rs9349379 in the phosphatase and actin regulator 1 gene, PHACTR1, (Beta = 0.30; 95% CI = 0.22-0.40; p = 4.67x10-11). Both SNPs remained nominally significant in dichotomized analyses for the presence of any CAC (odds ratiors1537373 (OR) = 1.19; 95% CI = 1.07-1.31; p = 0.001 and ORrs9349379 = 1.26; 95% CI = 1.14-1.40); p = 1.5x10-5). Fine mapping of the 9p21 and PHACTR1 gene region revealed several other SNPs that were strongly associated with CAC.
We demonstrate that SNPs near 9p21 and in PHACTR1 that have previously been shown to be associated with CHD are strongly associated with CAC in the Heinz Nixdorf Recall Study cohort. Our findings suggest that the 9p21 and 6q24 loci might be involved in cardiac outcome via promoting development of atherosclerosis in the coronary arteries.
Coronary heart disease; Coronary artery calcification; Cohort study; Polymorphism; Metabochip
The microsomal triglyceride transfer protein (MTTP) is encoded by the MTTP gene that is regulated by cholesterol in humans. Previous studies investigating the effect of MTTP on ischemic heart disease have produced inconsistent results. Therefore, we have tested the hypothesis that the rare allele of the -164T > C polymorphism in MTTP alters the risk of cardiovascular disease (CVD), depending on the cholesterol levels.
The -164T > C polymorphism was genotyped in a case-cohort study (193 incident myocardial infarction (MI) and 131 incident ischemic stroke (IS) cases and 1 978 non-cases) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam study, comprising 27 548 middle-aged subjects. The Heinz Nixdorf Recall study (30 CVD cases and 1 188 controls) was used to replicate our findings.
Genotype frequencies were not different between CVD and CVD free subjects (P = 0.79). We observed an interaction between the -164T > C polymorphism and total cholesterol levels in relation to future CVD. Corresponding stratified analyses showed a significant increased risk of CVD (HRadditve = 1.38, 95% CI: 1.07 to 1.78) for individuals with cholesterol levels <200 mg/dL in the EPIC-Potsdam study. HRadditive was 1.06, 95% CI: 0.33 to 3.40 for individuals in the Heinz Nixdorf Recall study. A borderline significant decrease in CVD risk was observed in subjects with cholesterol levels ≥200 mg/dL (HRadditve = 0.77, 95% CI: 0.58 to 1.03) in the EPIC-Potsdam study. A similar trend was observed in the independent cohort (HRadditve = 0.60, 95% CI: 0.29 to 1.25).
Our study suggests an interaction between MTTP -164T > C functional polymorphism with total cholesterol levels. Thereby risk allele carriers with low cholesterol levels may be predisposed to an increased risk of developing CVD, which seems to be abolished among risk allele carriers with high cholesterol levels.
Epidemiology; Genetics; Myocardial infarction; Ischemic stroke; Cholesterol; Additive interaction
We evaluated risk factors associated with chronic headache (CH) such as age, gender, smoking, frequent drinking of alcoholic beverages (drinking), obesity, education and frequent intake of acute pain drugs to test their usefulness in clinical differentiation between chronic migraine (CM) and chronic tension-type headache (CTTH).
We used baseline data from the population-based German Headache Consortium Study including 9,944 participants aged 18–65 years, screened 2003–2005, using validated questionnaires. CM and CTTH were defined according to IHS criteria. Multinominal logistic regression analyses were used to investigate the association of CM or CTTH with risk factors by estimating odds ratios (OR) and 95% confidence intervals (95%CI).
The prevalence of CH was 2.6% (N = 255, mean age 46 ± 14.1 years, 65.1% women), CM 1.1% (N = 108, 45 ± 12.9 years, 73.1%), CTTH 0.5% (N = 50, 49 ± 13.9 years, 48.0%). Participants with CM compared to CTTH were more likely to be female (OR: 2.34, 95%CI: 1.00-5.49) and less likely to drink alcohol (0.31, 0.09-1.04). By trend they seemed more likely to smoke (1.81, 0.76-4.34), to be obese (1.85, 0.54-6.27), to report frequent intake of acute pain drugs (1.68, 0.73-3.88) and less likely to be low educated (0.72, 0.27-1.97).
We concluded that the careful assessment of different risk factors might aid in the clinical differentiation between CM and CTTH.
Chronic migraine; Chronic tension-type headache; Epidemiology; Risk factors
Introduction. The Department for Internal and Integrative Medicine in Essen utilizes mind/body medical elements in order to empower patients with chronic diseases to better cope with their symptoms and to adopt a healthy lifestyle. This study explored the influence and predictors of a 2-week integrative treatment program on patients' quality of life. Methods. This observational study was conducted with inpatients as part of the quality assurance program. Patients' quality of life, psychological symptoms, and health locus of control were measured on admission and discharge and again 3, 6, and 12 months after discharge. Regression analyses were conducted to determine the factors predicting improved quality of life. Results. Data from 2486 inpatients treated in 2001–2004 were included (80% female, mean age 53.9 ± 14.3 years). Response rates decreased to 50% at 12 months. Small-to-moderate effects were found on patients' quality of life, anxiety, and depression. Patients' internal locus of control significantly increased. Improved quality of life was mainly predicted by lower baseline scores. Conclusion. Results of this study suggest that a 2-week inpatient treatment might sustainably reduce patients' symptoms and increase their quality of life; however, conclusions are only preliminary. More research is needed to enable the effectiveness to be judged conclusively.
Objectives: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans. Methods: We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets. Results: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing or conducting meta-analysis. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians. Conclusion: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns.
glioma; candidate SNP association study; ancestry informative markers; admixture; race; ethnicity; brain cancer
Hypertension and dyslipidemia are often insufficiently controlled in persons with type 2 diabetes (T2D) in Germany. In the current study we evaluated individual characteristics that are assumed to influence the adequate treatment and control of hypertension and dyslipidemia and aimed to identify the patient group with the most urgent need for improved health care.
The analysis was based on the DIAB-CORE project in which cross-sectional data from five regional population-based studies and one nationwide German study, conducted between 1997 and 2006, were pooled. We compared the frequencies of socio-economic and lifestyle factors along with comorbidities in hypertensive participants with or without the blood pressure target of < 140/90 mmHg. Similar studies were also performed in participants with dyslipidemia with and without the target of total cholesterol/HDL cholesterol ratio < 5. Furthermore, we compared participants who received antihypertensive/lipid lowering treatment with those who were untreated. Univariable and multivariable logistic regression models were used to assess the odds of potentially influential factors.
We included 1287 participants with T2D of whom n = 1048 had hypertension and n = 636 had dyslipidemia. Uncontrolled blood pressure was associated with male sex, low body mass index (BMI), no history of myocardial infarction (MI) and study site. Uncontrolled blood lipid levels were associated with male sex, no history of MI and study site. The odds of receiving no pharmacotherapy for hypertension were significantly greater in men, younger participants, those with BMI < 30 kg/m2 and those without previous MI or stroke. Participants with dyslipidemia received lipid lowering medication less frequently if they were male and had not previously had an MI. The more recent studies HNR and CARLA had the greatest numbers of well controlled and treated participants.
In the DIAB-CORE study, the patient group with the greatest odds of uncontrolled co-morbidities and no pharmacotherapy was more likely comprised of younger men with low BMI and no history of cardiovascular disease.
Type 2 Diabetes; Comorbidities; Hypertension; Dyslipidemia; Adherence to guidelines; Sex differences
While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case–control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, Pc = 7.72 × 10−8 and 2.09 × 10−8, respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.
Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.
While most genome-wide association studies (GWAS) focus on the identification of susceptibility loci for a specific disease, this hypothesis-free approach also enables the identification of unexpected associations between different diseases by taking advantage of the previously published GWAS associations. Androgenetic Alopecia (AGA, also known as male pattern baldness) is the most common type of hair loss in humans. Parkinson's disease is reported to occur more commonly in men than in women; however, there are no studies investigating the link between AGA and Parkinson's disease. Here, we show that a specific genetic locus, chromosome 17q21.31, which is associated with Parkinson's disease, is also a susceptibility locus for early-onset AGA. We further investigate the association between early-onset AGA and Parkinson's disease, irrespective of genotype, directly in a large-scale web-based study. We find that men with early-onset AGA have 28% higher risk of developing Parkinson's disease. The early-onset AGA locus on chromosome 17q21.31 has also been linked to decreased fertility previously. Future studies of this locus may implicate novel biological pathways affecting these three conditions.
Although most deaths among patients with type 2 diabetes (T2D) are attributable to cardiovascular disease, modifiable cardiovascular risk factors appear to be inadequately treated in medical practice. The aim of this study was to describe hypertension, dyslipidemia and medical treatment of these conditions in a large population-based sample.
The present analysis was based on the DIAB-CORE project, in which data from five regional population-based studies and one nationwide German study were pooled. All studies were conducted between 1997 and 2006. We assessed the frequencies of risk factors and co-morbidities, especially hypertension and dyslipidemia, in participants with and without T2D. The odds of no or insufficient treatment and the odds of pharmacotherapy were computed using multivariable logistic regression models. Types of medication regimens were described.
The pooled data set comprised individual data of 15, 071 participants aged 45–74 years, including 1287 (8.5%) participants with T2D. Subjects with T2D were significantly more likely to have untreated or insufficiently treated hypertension, i.e. blood pressure of > = 140/90 mmHg (OR = 1.43, 95% CI 1.26-1.61) and dyslipidemia i.e. a total cholesterol/HDL-cholesterol ratio > = 5 (OR = 1.80, 95% CI 1.59-2.04) than participants without T2D. Untreated or insufficiently treated blood pressure was observed in 48.9% of participants without T2D and in 63.6% of participants with T2D. In this latter group, 28.0% did not receive anti-hypertensive medication and 72.0% were insufficiently treated. In non-T2D participants, 28.8% had untreated or insufficiently treated dyslipidemia. Of all participants with T2D 42.5% had currently elevated lipids, 80.3% of these were untreated and 19.7% were insufficiently treated.
Blood pressure and lipid management fall short especially in persons with T2D across Germany. The importance of sufficient risk factor control besides blood glucose monitoring in diabetes care needs to be emphasized in order to prevent cardiovascular sequelae and premature death.
Type 2 Diabetes; Hypertension; Dyslipidemia; Adherence to guidelines; Pharmacological treatment
Background: Recent studies have shown an association of short-term exposure to fine particulate matter (PM) with transient increases in blood pressure (BP), but it is unclear whether long-term exposure has an effect on arterial BP and hypertension.
Objectives: We investigated the cross-sectional association of residential long-term PM exposure with arterial BP and hypertension, taking short-term variations of PM and long-term road traffic noise exposure into account.
Methods: We used baseline data (2000–2003) on 4,291 participants, 45–75 years of age, from the Heinz Nixdorf Recall Study, a population-based prospective cohort in Germany. Urban background exposure to PM with aerodynamic diameter ≤ 2.5 μm (PM2.5) and ≤ 10 μm (PM10) was assessed with a dispersion and chemistry transport model. We used generalized additive models, adjusting for short-term PM, meteorology, traffic proximity, and individual risk factors.
Results: An interquartile increase in PM2.5 (2.4 μg/m3) was associated with estimated increases in mean systolic and diastolic BP of 1.4 mmHg [95% confidence interval (CI): 0.5, 2.3] and 0.9 mmHg (95% CI: 0.4, 1.4), respectively. The observed relationship was independent of long-term exposure to road traffic noise and robust to the inclusion of many potential confounders. Residential proximity to high traffic and traffic noise exposure showed a tendency toward higher BP and an elevated prevalence of hypertension.
Conclusions: We found an association of long-term exposure to PM with increased arterial BP in a population-based sample. This finding supports our hypothesis that long-term PM exposure may promote atherosclerosis, with air-pollution–induced increases in BP being one possible biological pathway.
atherosclerosis; environmental epidemiology; hypertension; particulate matter; traffic emissions
Background: Secondhand smoke (SHS) consists of fine particulate matter, carcinogens, and various toxins that affect large parts of the population. SHS increases the risk for acute cardiovascular events and may contribute to the development of atherosclerosis.
Objectives: We investigated the association of SHS with coronary artery calcification (CAC).
Methods: In this cross-sectional analysis, we used baseline data (2000–2003) from 1,766 never-smokers without clinically manifested coronary heart disease, 45–75 years of age, from the Heinz Nixdorf Recall Study, an ongoing, prospective, population-based cohort study in Germany. Self-reported frequent SHS at home, at work, and in other places was assessed by questionnaire. CAC scores were derived based on electron-beam computed tomography. We conducted multiple linear regression analysis using exposure to SHS as the explanatory variable and ln(CAC+1) as the response variable. We conducted logistic regression to estimate the odds ratio (OR) for presence of any CAC.
Results: Frequent exposure to SHS was reported by 21.5% of participants. After adjustment for age, sex, and socioeconomic status, CAC + 1 was 21.1% [95% confidence interval (CI): –5.5%, 55.2%] higher in exposed than in unexposed participants. After adjusting for other cardiovascular risk factors, the association was attenuated (15.4%; 95% CI: –9.6%, 47.2%). SHS exposure was also associated with a CAC score > 0 (fully adjusted OR = 1.38; 95% CI: 1.03, 1.84).
Conclusions: Self-reported frequent exposure to SHS was associated with subclinical coronary atherosclerosis in our cross-sectional study population. Considering the widespread exposure and the clinical relevance of coronary atherosclerosis, this result, if confirmed, is of public health importance.
cardiovascular atherosclerosis; comparative risk assessment; environmental epidemiology; population health; secondhand smoke
Social relations have repeatedly been found to be an important determinant of health. However, it is unclear whether the association between social relations and health is consistent throughout different status groups. It is likely that health effects of social relations vary in different status groups, as stated in the hypothesis of differential vulnerability. In this analysis we explore whether socioeconomic status (SES) moderates the association between social relations and health.
In the baseline examination of the Heinz Nixdorf Recall study, conducted in a dense populated Western German region (N = 4,814, response rate 56%), SES was measured by income and education. Social relations were classified by using both structural as well as functional measures. The Social Integration Index was used as a structural measure, whilst functional aspects were assessed by emotional and instrumental support. Health was indicated by self-rated health (1 item) and a short version of the CES-D scale measuring the frequency of depressive symptoms. Based on logistic regression models we calculated the relative excess risk due to interaction (RERI) which indicates existing moderator effects.
Our findings show highest odds ratios (ORs) for both poor self-rated health and more frequent depressive symptoms when respondents have a low SES as well as inappropriate social relations. For example, respondents with low income and a low level of social integration have an OR for a high depression score of 2.85 (95% CI 2.32-4.49), compared to an OR of 1.44 (95% CI 1.12-1.86) amongst those with a low income but a high level of social integration and an OR of 1.72 (95% CI 1.45-2.03) amongst respondents with high income but a low level of social integration. As reference group those reporting high income and a high level of social integration were used.
The analyses indicate that the association of social relations and subjective health differs across SES groups as we find moderating effects of SES. However, results are inconsistent as nearly all RERI scores are positive but do not reach a significant level. Also moderating effects vary between women and men and depending on the indicators of SES and social relations used. Thus, the hypothesis of differential vulnerability can only partially be supported. In terms of practical implications, psychosocial and health interventions aiming towards the enhancement of social relations should especially consider the situation of the socially deprived.
Blood glucose (BG) is usually measured after a caloric restriction of at least 8 h; however evidence-based recommendations for the duration of a fasting status are missing. Here we analyze the effect of fasting duration on levels of BG to determine the minimal fasting duration to achieve comparable BG levels to conventional fasting measurements. We used data of a cross-sectional study on primary care patients, performed in October 2005. We included 28,024 individuals (age-range 18–99 years; 63% women) without known diabetes mellitus and without missing data for BG and fasting status. We computed general linear models, adjusting for age, sex, time of blood withdrawal, systolic blood pressure, waist circumference, total- and HDL-cholesterol, physical activity, smoking, intake of beta-blocker and alcohol. We tested the intra-individual variability with respect to fasting status. Overall, the mean BG differed only slightly between individuals fasting ≥8 h and those fasting <8 h (men: 5.1 ± 0.8 mmol/L versus 5.2 ± 1.2 mmol/L; women: 4.9 ± 0.7 mmol/L, 5.0 ± 1.0 mmol/L). After 3 h of fasting differences of BG diminished in men to −0.08 mmol/L (95%-CI: −0.15; −0.01 mmol/L), in women to −0.07 mmol/L (−0.12; −0.03 mmol/L) compared to individuals fasting ≥8 h. Noteworthy, age, time of day of blood withdrawal, physical activity, and intake of hard liquor influenced BG levels considerably. Our data challenge the necessity for a fasting duration of ≥8 h when measuring blood glucose, suggesting a random sampling or a fasting duration of 3 h as sufficient. Rather, our study indicates that essentially more effort on the assessment of additional external/internal factors on BG levels is necessary.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-011-9608-z) contains supplementary material, which is available to authorized users.
Blood glucose; Risk assessment; Nonfasting; Cross-sectional study
Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (p=5.12 × 10−9, OR 1.23 [1.150-1.324]) in a genome-wide association study of 2,748 migraineurs from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis p-value of 1.60 × 10−11 (OR 1.18 [1.127 – 1.244]). rs1835740 is located between the astrocyte elevated gene 1 (MTDH/AEG-1) and plasma glutamate carboxypeptidase (PGCP). In an expression quantitative trait study in lymphoblastoid cell lines transcript levels of the MTDH/AEG-1 were found to have a significant correlation to rs1835740. Our data establish rs1835740 as the first genetic risk factor for migraine.
Atrial fibrillation (AF) is the most common sustained arrhythmia. A subset of patients with lone AF have no overt heart disease and an increased heritability of AF. We sought to identify common genetic variants underlying lone AF. Cases were from the German AF Network, Heart and Vascular Health Study, Atherosclerosis Risk in Communities Study, Cleveland Clinic, and Massachusetts General Hospital. Subjects were genotyped, HapMap SNPs imputed, and age- sex- and hypertension-adjusted analyses performed. A meta-analysis was conducted using 1,335 cases of lone AF and 12,844 referents. A novel locus on chromosome 1q21 was identified, and the most significant SNP, rs13376333, had an adjusted odds ratio of 1.56 (P=6.3×10−12). This association was replicated in two cohorts with lone AF for an overall odds ratio of 1.52 (P=1.83×10−21). Rs13376333 is intronic to KCNN3, a potassium channel involved in atrial repolarization. KCNN3 represents a novel potential therapeutic target in the treatment of AF.
Based on the AHA/NHLBI-definition three out of five cardiometabolic traits must be present for the diagnosis of the metabolic syndrome (MetS), resulting in 16 different combination types. The associated cardiovascular risk may however be different and specific combination may be indicative of an increased risk, furthermore little is known to which extent these 16 combinations contribute to the overall prevalence of MetS. Here we assessed the prevalence of all 16 combination types of MetS, analyzed the impact of age and gender on prevalence rates, and estimated the 10-year risk of fatal and non-fatal myocardial infarction (MI) of each MetS combination type.
We used data of the German Metabolic and Cardiovascular Risk Project (GEMCAS), a cross-sectional study, performed during October 2005, including 35,869 participants (aged 18-99 years, 61% women). Age-standardized prevalence and 10-year PROCAM and ESC risk scores for MI were calculated.
In both men and women the combination with elevated waist-circumference, blood pressure and glucose (WC-BP-GL) was the most frequent combination (28%), however a distinct unequal distribution was observed regarding age and sex. Any combination with GL was common in the elderly, whereas any combination with dyslipidemia and without GL was frequent in the younger. Men without MetS had an estimated mean 10-year risk of 4.7% (95%-CI: 4.5%-4.8%) for MI (PROCAM), whereas the mean 10-year risk of men with MetS was clearly higher (age-standardized 7.9%; 7.8-8.0%). In women without MetS the mean 10-year risk for MI was 1.1%, in those with MetS 2.3%. The highest impact on an estimated 10-year risk for MI (PROCAM) was observed with TG-HDL-GL-BP in both sexes (men 14.7%, women 3.9%). However, we could identify combinations with equal risks of non-fatal and fatal MI compared to participants without MetS.
We observed large variations in the prevalence of all 16 combination types and their association to cardiovascular risk. The importance of different combinations of MetS changes with age and between genders putting emphasis on a tailored approach towards very young or very old subjects. This knowledge may guide clinicians to effectively screen individuals and prioritize diagnostic procedures depending on age and gender.
Long-term exposure to urban air pollution may accelerate atherogenesis, but mechanisms are still unclear. The induction of a low-grade systemic inflammatory state is a plausible mechanistic pathway. Objectives: We analyzed the association of residential long-term exposure to particulate matter (PM) and high traffic with systemic inflammatory markers.
We used baseline data from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study of 4,814 participants that started in 2000. Fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposure based on a small-scale dispersion and chemistry transport model was assigned to each home address. We calculated distances between residences and major roads. Long-term exposure to air pollution (annual PM2.5 and distance to high traffic) and concentration of inflammatory markers [high-sensitivity C-reactive protein (hs-CRP) and fibrinogen] on the day of the baseline visit were analyzed with sex-stratified multiple linear regression, controlling for individual-level risk factors.
In the adjusted analysis, a cross-sectional exposure difference of 3.91 μg/m3 in PM2.5 (interdecile range) was associated with increases in hs-CRP of 23.9% [95% confidence interval (CI), 4.1 to 47.4%] and fibrinogen of 3.9% (95% CI, 0.3 to 7.7%) in men, whereas we found no association in women. Chronic traffic exposure was not associated with inflammatory markers. Short-term exposures to air pollutants and temperature did not influence the results markedly.
Our study indicates that long-term residential exposure to high levels of PM2.5 is associated with systemic inflammatory markers in men. This might provide a link between air pollution and coronary atherosclerosis.
air quality; cardiovascular disease; epidemiology; inflammation; roadway proximity
On the basis of the Framingham risk algorithm, overestimation of clinical events has been reported in some European populations. Electron-beam computed tomography-derived quantification of coronary artery calcification (CAC) allows for noninvasive assessment of coronary atherosclerosis in the general population and may thus add important in vivo information on the path from risk factor exposure to formation of clinical events. The current study was undertaken to compare the relationship between risk factors and subclinical coronary atherosclerosis between non-Hispanic white cohorts in Germany and US-America, the hypothesis being that subclinical coronary atherosclerosis might be less prevalent in Europe at the same level of classical risk factor exposure.
The Heinz Nixdorf Recall (HNR) study, conducted in the German Ruhr area and the Epidemiology of Coronary Calcification (ECAC) study, conducted in Olmsted County, Minnesota, both recruited large unselected cohorts, men and women aged 45 – 74 years, from the general population. All subjects with no history of coronary artery disease (CAD) or stroke were included (n = 3,120 in HNR, n = 703 in ECAC). Coronary risk factors were assessed by personal and computer-assisted interviews and direct laboratory measurements. Cardiovascular medication use (antihypertensive, lipid-lowering, and anti-diabetic) was noted. CAC scores were determined using the Agatston method in an identical fashion in both studies.
Adverse levels of risk factors were more prevalent, and the Framingham risk score was higher (10.6 ± 7.6 vs. 9.3 ± 7.1, p < 0.001) in HNR than ECAC, respectively. There was no difference in body mass index (BMI). CAC scores were greater in HNR than in ECAC (mean values, 155.7 ± 423.0 versus 107.2 ± 280.0; median values, 11.9 versus 2.4; p < 0.001, respectively). When subjects were matched on CAD risk factors, presence and quantity of CAC were similar in the 2 cohorts. Risk factors significantly associated with CAC score in both studies included: age, male sex, current and former smoking, systolic blood pressure, and non HDL-cholesterol. Inferences were similar after excluding subjects using lipid- or blood pressure-lowering medications. Using the same risk factor variables for modelling, the predicted CAC scores were comparable in both cohorts.
In the higher-risk German cohort, presence and quantity of CAC were greater than in the lower-risk US-American cohort. Risk factor associations, however, with CAC were very similar in both unselected populations. As opposed to studies concerning clinical endpoints, we could not demonstrate a relative increase in subclinical coronary atherosclerosis in the US-American cohort.
Current guidelines from the European Society of Cardiology (ESC) define low thresholds for the diagnosis of dyslipidemia using total cholesterol (TC) and LDL-cholesterol (LDL-C) to guide treatment. Although being mainly a prevention tool, its thresholds are difficult to meet in clinical practice, especially primary care.
In a nationwide study with 1,511 primary care physicians and 35,869 patients we determined the prevalence of dyslipidemia, its recognition, treatment, and control rates. Diagnosis of dyslipidemia was based on TC and LDL-C. Basic descriptive statistics and prevalence rate ratios, as well as 95% confidence intervals were calculated.
Dyslipidemia was highly frequent in primary care (76% overall). 48.6% of male and 39.9% of female patients with dyslipidemia was diagnosed by the physicians. Life style intervention did however control dyslipidemia in about 10% of patients only. A higher proportion (34.1% of male and 26.7% female) was controlled when receiving pharmacotherapy. The chance to be diagnosed and subsequently controlled using pharmacotherapy was higher in male (PRR 1.15; 95%CI 1.12–1.17), in patients with concomitant cardiovascular risk factors, in patients with hypertension (PRR 1.20; 95%CI 1.05–1.37) and cardiovascular disease (PRR 1.46; 95%CI 1.29–1.64), previous myocardial infarction (PRR 1.32; 95%CI 1.19–1.47), and if patients knew to be hypertensive (PRR 1.18; 95%CI 1.04–1.34) or knew about their prior myocardial infarction (PRR 1.17; 95%CI 1.23–1.53).
Thresholds of the ESC seem to be difficult to meet. A simple call for more aggressive treatment or higher patient compliance is apparently not enough to enhance the proportion of controlled patients. A shift towards a multifactorial treatment considering lifestyle interventions and pharmacotherapy to reduce weight and lipids may be the only way in a population where just to be normal is certainly not ideal.
Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR).
Methods and results
The measured CAC in 2220 MESA participants were compared with those in 3126 HNR participants with the inclusion criteria such as age 45–75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72–0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19–1.63), since many HNR participants have small (near zero) CAC values.
The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort.
Epidemiology; Atherosclerosis; Coronary artery calcium; Risk factors; Screening
Obesity is one of the greatest challenges in primary health care. The BMI describes fat mass and waist circumference (WC) fat distribution and total metabolic and cardiovascular risk. It was aim of the present study to assess the prevalence of a) overweight and obesity and b) an increased and high WC in adults seeking primary care in Germany and to describe the associations of both measures with cardiovascular risk factors and prognosis.
This was a point prevalence study with 1,511 primary care physicians and 35,869 adult patients in 2005. Bodyweight, height and waist circumference was measured and blood samples taken to determine the presence of cardiovascular risk factors, including lipids, blood pressure, fasting glucose, low physical activity, smoking and family history of myocardial infarction. We calculated rate ratios stratified for age and gender.
There was a high prevalence of overweight (45.7% male [95%CI 44.9–46.5]; 30.6% female [95%CI 30.0–31.2]) and obesity (24.7% male [95%CI 24.0–25.4]; 23.3% female [95%CI 22.8–23.9]). 36.4% of male [95%CI 35.6–37.2] and 41.5% of female [95%CI 40.8–42.1] had a high WC (male > 102, female > 88 cm). A high WC in addition to an overweight BMI identified patients with more risk factors (male: mean of 3.93 risk factors (RF) at a WC > 102 cm vs. 2.88 RF in patients ≤ 94 cm; female 3.58 RF at a WC > 88 cm vs. 2.41 RF ≤ 80 cm).
There is a high prevalence of obesity (24.7% of male and 23.3% of female) and, in particular, abdominal obesity (36.4% of male and 41.5% of female) in adults attending a primary care physician in Germany. The determination of the BMI is sufficient to assess risk in normal weight and obese patients, while a high WC identifies high risk patients from within the overweight group.
Previous studies have shown that deprived neighbourhoods have higher cardiovascular mortality and morbidity rates. Inequalities in the distribution of behaviour related risk factors are one possible explanation for this trend. In our study, we examined the association between cardiovascular risk factors and neighbourhood characteristics. To assess the consistency of associations the design is cross-national with data from nine industrial towns from the Czech Republic and Germany.
We combined datasets from two population based studies, one in Germany ('Heinz Nixdorf Recall (HNR) Study'), and one in the Czech Republic ('Health, Alcohol and Psychosocial Factors in Eastern Europe (HAPIEE) Study'). Participation rates were 56% in the HNR and 55% in the HAPIEE study. The subsample for this particular analysis consists of 11,554 men and women from nine German and Czech towns. Census based information on social characteristics of 326 neighbourhoods were collected from local administrative authorities. We used unemployment rate and overcrowding as area-level markers of socioeconomic status (SES). The cardiovascular risk factors obesity, hypertension, smoking and physical inactivity were used as response variables. Regression models were complemented by individual-level social status (education) and relevant covariates.
Smoking, obesity and low physical activity were more common in deprived neighbourhoods in Germany, even when personal characteristics including individual education were controlled for. For hypertension associations were weak. In the Czech Republic associations were observed for smoking and physical inactivity, but not for obesity and hypertension when individual-level covariates were adjusted for. The strongest association was found for smoking in both countries: in the fully adjusted model the odds ratio for 'high unemployment rate' was 1.30 [95% CI 1.02–1.66] in the Czech Republic and 1.60 [95% CI 1.29–1.98] in Germany.
In this comparative study, the effects of neighbourhood deprivation varied by country and risk factor; the strongest and most consistent effects were found for smoking. Results indicate that area level SES is associated with health related lifestyles, which might be a possible pathway linking social status and cardiovascular disease. Individual-level education had a considerable influence on the association between neighbourhood characteristics and risk factors.