Karin Halina Greiser

Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data

CONTEXT Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease

Background—Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD). Methods and Results—A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6×10−50 and 6.2×10−25, respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4×10−13). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2×10−6; rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4×10−6), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3×10−5). Conclusion—Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

Regional differences in the prevalence of known Type 2 diabetes mellitus in 45–74 years old individuals: Results from six population‐based studies in Germany (DIAB‐CORE Consortium)

Diabet. Med. 29, e88–e95 (2012)

Cardiovascular disease, risk factors and heart rate variability in the elderly general population: Design and objectives of the CARdiovascular disease, Living and Ageing in Halle (CARLA) Study

BackgroundThe increasing burden of cardiovascular diseases (CVD) in the ageing population of industrialized nations requires an intensive search for means of reducing this epidemic. In order to improve prevention, detection, therapy and prognosis of cardiovascular diseases on the population level in Eastern Germany, it is necessary to examine reasons for the East-West gradient of CVD morbidity and mortality, potential causal mechanisms and prognostic factors in the elderly.Psychosocial and nutritional factors have previously been discussed as possible causes for the unexplained part of the East-West gradient. A reduced heart rate variability appears to be associated with cardiovascular disease as well as with psychosocial and other cardiovascular risk factors and decreases with age. Nevertheless, there is a lack of population-based data to examine the role of heart rate variability and its interaction with psychosocial and nutritional factors regarding the effect on cardiovascular disease in the ageing population. There also is a paucity of epidemiological data describing the health situation in Eastern Germany. Therefore, we conduct a population-based study to examine the distribution of CVD, heart rate variability and CVD risk factors and their associations in an elderly East German population. This paper describes the design and objectives of the CARLA Study.Methods/designFor this study, a random sample of 45–80 year-old inhabitants of the city of Halle (Saale) in Eastern Germany was drawn from the population registry. By the end of the baseline examination (2002–2005), 1750 study participants will have been examined. A multi-step recruitment strategy aims at achieving a 70 % response rate.Detailed information is collected on own and family medical history, socioeconomic, psychosocial, behavioural and biomedical factors. Medical examinations include anthropometric measures, blood pressure of arm and ankle, a 10-second and a 20-minute electrocardiogram, a general physical examination, an echocardiogram, and laboratory analyses of venous blood samples. On 200 participants, a 24-hour electrocardiogram is recorded. A detailed system of quality control ensures high data quality. A follow-up examination is planned.DiscussionThis study will help to elucidate pathways to CVD involving autonomic dysfunction and lifestyle factors which might be responsible for the CVD epidemic in some populations.

Health-related quality of life in subjects with and without Type 2 diabetes: pooled analysis of five population-based surveys in Germany.

Diabet. Med. 29, 646–653 (2012)

Prevalence of symptomatic heart failure with reduced and with normal ejection fraction in an elderly general population-the CARLA study.

Background/Objectives Chronic heart failure (CHF) is one of the most important public health concerns in the industrialized world having increasing incidence and prevalence. Although there are several studies describing the prevalence of heart failure with reduced ejection fraction (HFREF) and heart failure with normal ejection fraction (HFNEF) in selected populations, there are few data regarding the prevalence and the determinants of symptomatic heart failure in the general population. Methods Cross-sectional data of a population-based German sample (1,779 subjects aged 45–83 years) were analyzed to determine the prevalence and determinants of chronic SHF and HFNEF defined according to the European Society of Cardiology using symptoms, echocardiography and serum NT-proBNP. Prevalence was age-standardized to the German population as of December 31st, 2005. Results The overall age-standardized prevalence of symptomatic CHF was 7.7% (95%CI 6.0–9.8) for men and 9.0% (95%CI 7.0–11.5) for women. The prevalence of CHF strongly increased with age from 3.0% among 45–54- year-old subjects to 22.0% among 75–83- year-old subjects. Symptomatic HFREF could be shown in 48% (n = 78), symptomatic HFNEF in 52% (n = 85) of subjects with CHF. The age-standardized prevalence of HFREF was 3.8 % (95%CI 2.4–5.8) for women and 4.6 % (95%CI 3.6–6.3) for men. The age-standardized prevalence of HFNEF for women and men was 5.1 % (95%CI 3.8–7.0) and 3.0 % (95%CI 2.1–4.5), respectively. Persons with CHF were more likely to have hypertension (PR = 3.4; 95%CI 1.6–7.3) or to have had a previous myocardial infarction (PR = 2.5, 95%CI 1.8–3.5). Conclusion The prevalence of symptomatic CHF appears high in this population compared with other studies. While more women were affected by HFNEF than men, more male subjects suffered from HFREF. The high prevalence of symptomatic CHF seems likely to be mainly due to the high prevalence of cardiovascular risk factors in this population.

Whole-Body MR Imaging in the German National Cohort: Rationale, Design, and Technical Background

PURPOSE To detail the rationale, design, and future perspective of implementing whole-body magnetic resonance (MR) imaging in the German National Cohort, a large multicentric population-based study. MATERIALS AND METHODS All institutional review boards approved the study, and informed consent is obtained before study enrollment. Participants are enrolled from a random sample of the general population at five dedicated imaging sites among 18 recruitment centers. MR imaging facilities are equipped with identical 3.0-T imager technology and use uniform MR protocols. Imager-specific hardware and software settings remained constant over the study period. On-site and centralized measures of image quality enable monitoring of completeness of the acquisitions and quality of each of the MR sequences. Certified radiologists read all MR imaging studies for presence of incidental findings according to predefined algorithms. RESULTS Over a 4-year period, six participants per day are examined at each center, totaling a final imaging cohort of approximately 30 000 participants. The MR imaging protocol is identical for each site and comprises a set of 12 native series to cover neurologic, cardiovascular, thoracoabdominal, and musculoskeletal imaging phenotypes totaling approximately 1 hour of imaging time. A dedicated analysis platform as part of a central imaging core incorporates a thin client-based integrative and modular data handling platform to enable multicentric off-site image reading for incidental findings. Scientific analysis will be pursued on a per-project hypothesis-driven basis. CONCLUSION Population-based whole-body MR imaging as part of the German National Cohort will serve to compile a comprehensive image repository, will provide insight into physiologic variants and subclinical disease burden, and has the potential to enable identification of novel imaging biomarkers of risk.

Association of childhood and adult socioeconomic indicators with cardiovascular risk factors and its modification by age: the CARLA Study 2002-2006.

BackgroundThe influence of socioeconomic status (SES) on cardiovascular diseases and risk factors is widely known, although the role of different SES indicators is not fully understood. The aim of this study was to investigate the role of different SES indicators for cardiovascular disease risk factors in a middle and old aged East German population.MethodsCross-sectional data of an East German population-based cohort study (1779 men and women aged 45 to 83) were used to assess the association of childhood and adulthood SES indicators (childhood SES, education, occupational position, income) with cardiovascular risk factors. Adjusted means and odds ratios of risk factors by SES indicators with 95% confidence intervals (CI) were calculated by linear and logistic regression models, stratified by sex. The interaction effect of education and age on cardiovascular risk factors was tested by including an interaction term.ResultsIn age-adjusted models, education, occupational position, and income were statistically significantly associated with abdominal obesity in men, and with smoking in both sexes. Men with low education had a more than threefold risk of being a smoker (OR 3.44, CI 1.58-7.51). Low childhood SES was associated with higher systolic blood pressure and abdominal obesity in women (OR 2.27, CI 1.18-4.38 for obesity); a non-significant but (in terms of effect size) relevant association of childhood SES with smoking was observed in men. In women, age was an effect modifier for education in the risk of obesity and smoking.ConclusionsWe found considerable differences in cardiovascular risk factors by education, occupational position, income, and partly by childhood social status, differing by sex. Some social inequalities levelled off in higher age. Longitudinal studies are needed to differentiate between age and birth cohort effects.

Time domain parameters can be estimated with less statistical error than frequency domain parameters in the analysis of heart rate variability

INTRODUCTION Measures of heart rate variability (HRV) can be divided in time domain and frequency domain parameters. It is frequently ignored that estimation of frequency-domain parameters is a 2-step procedure where statistical error from the first step (spectral estimation) is neglected in subsequent analyses. METHODS We performed a simulation study to quantify the statistical error by using frequency domain instead of time domain parameters. We generated tachograms from a stationary AR(1) process for a wide range of parameters and compared the resulting estimation error (in terms of precision and variability) for the standard deviation of normal RR intervals (SDNN) and low frequency (LF), high frequency (HF), and LF/HF power. RESULTS Estimation of frequency domain parameters is associated with (up to 10-fold) increased variability, as compared with the SDNN. Moreover, the SDNN has higher precision. CONCLUSION Frequency domain parameters should be applied in HRV analysis only if important physiological reasons suggest their use. If used, frequency domain parameters should be interpreted with caution, taking into account the statistical weaknesses of spectral estimation.

Regional and Neighborhood Disparities in the Odds of Type 2 Diabetes: Results From 5 Population-Based Studies in Germany (DIAB-CORE Consortium)

The objective of this study was to investigate the association between residential environment and type 2 diabetes. We pooled cross-sectional data from 5 population-based German studies (1997-2006): the Cardiovascular Disease, Living and Ageing in Halle Study, the Dortmund Health Study, the Heinz Nixdorf Recall Study, the Cooperative Health Research in the Region of Augsburg Study, and the Study of Health in Pomerania. The outcome of interest was the presence of self-reported type 2 diabetes. We conducted mixed logistic regression models in a hierarchical data set with 8,879 individuals aged 45-74 years on level 1; 226 neighborhoods on level 2; and 5 study regions on level 3. The analyses were adjusted for age, sex, social class, and employment status. The odds ratio for type 2 diabetes was highest in eastern Germany (odds ratio = 1.98, 95% confidence interval: 1.81, 2.14) and northeastern Germany (odds ratio = 1.58, 95% confidence interval: 1.40, 1.77) and lowest in southern Germany (reference) after adjustment for individual variables. Neighborhood unemployment rates explained a large proportion of regional differences. Individuals residing in neighborhoods with high unemployment rates had elevated odds of type 2 diabetes (odds ratio = 1.62, 95% confidence interval: 1.25, 2.09). The diverging levels of unemployment in neighborhoods and regions are an independent source of disparities in type 2 diabetes.