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Abstract Left atrial (LA) physiology and hemodynamics are intimately connected to cardiac and lung function in health and disease. This study examined the relationship between MRI-based left atrial (LA) size and function with MRI-based lung volume and pulmonary function testing (PFT) parameters in the population-based KORA study cohort of 400 participants without overt cardiovascular disease. MRI quantification assessed LA size/function in sequences with and without ECG synchronization, alongside lung volume. Regression analysis explored the relationship of LA with MRI lung volume and PFT parameters. Among 378 participants (average age 56.3 ± 9.2 years; 42.3% women), non-gated LA size averaged 16.8 cm2, while maximal and minimal LA size from gated measurements were 19.6 cm2 and 11.9 cm2 respectively. The average MRI-derived lung volume was 4.0 L, with PFT showing a total lung capacity of 6.2 L, residual lung volume of 2.1 L, and forced vital capacity of 4.1 L. Multivariate regression analysis, adjusted for age, gender, and cardiovascular risk factors, revealed an inverse association between maximum LA size, non-gated LA, and LA area fraction with lung volume (ß = − 0.03, p = 0.006; ß = − 0.03, p = 0.021; ß = − 0.01, p = 0.012), with no significant association with PFT parameters. This suggests that MRI-based assessment may offer greater sensitivity in detecting subclinical LA impairment than PFT.

Abstract Background Loss to follow-up in long-term epidemiological studies is well-known and often substantial. Consequently, there is a risk of bias to the results. The motivation to take part in an epidemiological study can change over time, but the ways to minimize loss to follow-up are not well studied. The Citizen Science approach offers researchers to engage in direct discussions with study participants and to integrate their opinions and requirements into cohort management. Methods Guided group discussions were conducted with study participants from the KORA cohort in the Augsburg Region in Germany, established 40 years ago, as well as a group of independently selected citizens. The aim was to look at the relevant aspects of health studies with a focus on long-term participation. A two-sided questionnaire was developed subsequently in a co-creation process and presented to 500 KORA participants and 2,400 employees of the research facility Helmholtz Munich. Results The discussions revealed that altruistic motivations, (i.e. supporting research and public health), personal benefits (i.e. a health check-up during a study examination), data protection, and information about research results in layman’s terms were crucial to ensure interest and long-term study participation. The results of the questionnaire confirmed these aspects and showed that exclusively digital information channels may be an obstacle for older and less educated people. Thus, paper-based media such as newsletters are still important. Conclusions The findings shed light on cohort management and long-term engagement with study participants. A long-term health study needs to benefit public and individual health; the institution needs to be trustworthy; and the results and their impact need to be disseminated in widely understandable terms and by the right means of communication back to the participants.

Abstract Background Obesity is associated with alterations in the hypothalamic–pituitary–adrenal (HPA) axis. Effects of glucocorticoids on adipose tissues appear to depend on the specific adipose depot, in which they take place. In this study, we aimed to investigate the role of MRI-based adrenal gland volume as an imaging marker in association with different adipose tissue compartments. Methods The study cohort derives from the population-based research platform KORA (Cooperative Health Research in the Augsburg Region, Germany) MRI sub-study, a cross-sectional sub-study investigating the interactions between subclinical metabolic changes and cardiovascular disease in a study sample of 400 participants. Originally, eligible subjects underwent a whole-body MRI. MRI-based segmentations were performed manually and semi-automatically for adrenal gland volume, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), epi- and pericardial fat and renal sinus fat. Hepatic and pancreatic lipid content were measured as pancreatic proton density fraction (PDFF) and MR-spectroscopic hepatic fat fraction (HFF). Multivariable linear regression analyses were performed. Results A number of 307 participants (56.2 ± 9.1 years, 60.3% male, 14.3% with type 2 diabetes (T2DM), 30.6% with obesity, 34.2% with hypertension) were included. In multivariable analyses, strong positive associations between adrenal gland volume and VAT, total adipose tissue (TAT) as well as HFF persisted after extensive step-wise adjustment for possible metabolic confounders (VAT: beta = 0.31, 95%-CI [0.71, 0.81], p

Abstract Aim of this study was to analyse the associations of cardiovascular health and adrenal gland volume as a rather new imaging biomarker of chronic hypothalamic–pituitary–adrenal (HPA) axis activation. The study population originates from the KORA population-based cross-sectional prospective cohort. 400 participants without known cardiovascular disease underwent a whole-body MRI. Manual segmentation of adrenal glands was performed on VIBE-Dixon gradient-echo sequence. MRI based evaluation of cardiac parameters was achieved semi-automatically. Cardiometabolic risk factors were obtained through standardized interviews and medical examination. Univariate and multivariate associations were derived. Bi-directional causal mediation analysis was performed. 351 participants were eligible for analysis (56 ± 9.1 years, male 58.7%). In multivariate analysis, significant associations were observed between adrenal gland volume and hypertension (outcome hypertension: Odds Ratio = 1.11, 95% CI [1.01, 1.21], p = 0.028), left ventricular remodelling index (LVRI) (outcome LVRI: β = 0.01, 95% CI [0.00, 0.02], p = 0.011), and left ventricular (LV) wall thickness (outcome LV wall thickness: β = 0.06, 95% CI [0.02, 0.09], p = 0.005). In bi-directional causal mediation analysis adrenal gland volume had a borderline significant mediating effect on the association between hypertension and LVRI (p = 0.052) as well as wall thickness (p = 0.054). MRI-based assessment of adrenal gland enlargement is associated with hypertension and LV remodelling. Adrenal gland volume may serve as an indirect cardiovascular imaging biomarker.

Abstract Background Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. Methods Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. Results Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. Conclusion This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Abstract Background and aims Atherosclerosis is the main cause of stroke and coronary heart disease (CHD), both leading mortality causes worldwide. Proteomics, as a high-throughput method, could provide helpful insights into the pathological mechanisms underlying atherosclerosis. In this study, we characterized the associations of plasma protein levels with CHD and with carotid intima-media thickness (CIMT), as a surrogate measure of atherosclerosis. Methods The discovery phase included 1000 participants from the KORA F4 study, whose plasma protein levels were quantified using the aptamer-based SOMAscan proteomics platform. We evaluated the associations of plasma protein levels with CHD using logistic regression, and with CIMT using linear regression. For both outcomes we applied two models: an age-sex adjusted model, and a model additionally adjusted for body mass index, smoking status, physical activity, diabetes status, hypertension status, low density lipoprotein, high density lipoprotein, and triglyceride levels (fully-adjusted model). The replication phase included a matched case-control sample from the independent KORA F3 study, using ELISA-based measurements of galectin-4. Pathway analysis was performed with nominally associated proteins (p-value

Abstract Background Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. Methods Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. Results Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41–0.56), while overweight (HR 2.03; 95% CI 1.41–2.94) and obesity (HR 1.89; 95% CI 1.02–3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40–0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. Conclusions Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.

Abstract Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process.

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics. Methods We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups. Results We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p

Abstract Background The reduction of myocardial infarction (MI) and narrowing the gap between the populations with and without diabetes are important goals of diabetes care. We analyzed time trends for sex-specific incidence rates (IR) of first MI (both non-fatal MI and fatal MI) as well as separately for first non-fatal MI and fatal MI in the population with and without diabetes. Methods Using data from the KORA myocardial infarction registry (Augsburg, Germany), we estimated age-adjusted IR in people with and without diabetes, corresponding relative risks (RR), and time trends from 1985 to 2016 using Poisson regression. Results There were 19,683 people with first MI (34% fatal MI, 71% men, 30% with diabetes) between 1985 and 2016. In the entire study population, the IR of first MI decreased from 359 (95% CI: 345–374) to 236 (226–245) per 100,000 person years. In men with diabetes, IR decreased only in 2013–2016. This was due to first non-fatal MI, where IR in men with diabetes increased until 2009–2012, and slightly decreased in 2013–2016. Overall, fatal MI declined stronger than first non-fatal MI corresponding to IRs. The RR of first MI substantially increased among men from 1.40 (1.22–1.61) in 1985–1988 to 2.60 (2.26–2.99) in 1997–2000 and moderately decreased in 2013–2016: RR: 1.75 (1.47–2.09). Among women no consistent time trend for RR was observed. Time trends for RR were similar regarding first non-fatal MI and fatal MI. Conclusions Over the study period, we found a decreased incidence of first MI and fatal MI in the entire study population. The initial increase of first non-fatal MI in men with diabetes needs further research. The gap between populations with and without diabetes remained.

Abstract Background Changes in serum metabolites in individuals with altered cardiac function and morphology may exhibit information about cardiovascular disease (CVD) pathway dysregulations and potential CVD risk factors. We aimed to explore associations of cardiac function and morphology, evaluated using magnetic resonance imaging (MRI) with a large panel of serum metabolites. Methods Cross-sectional data from CVD-free individuals from the population-based KORA cohort were analyzed. Associations between 3T-MRI-derived left ventricular (LV) function and morphology parameters (e.g., volumes, filling rates, wall thickness) and markers of carotid plaque with metabolite profile clusters and single metabolites as outcomes were assessed by adjusted multinomial logistic regression and linear regression models. Results In 360 individuals (mean age 56.3 years; 41.9% female), 146 serum metabolites clustered into three distinct profiles that reflected high-, intermediate- and low-CVD risk. Higher stroke volume (relative risk ratio (RRR): 0.53, 95%-CI [0.37; 0.76], p-value

Abstract Background Coronary heart disease (CHD) is a major global health concern, especially among individuals with type 2 diabetes (T2D). Given the crucial role of proteins in various biological processes, this study aimed to elucidate the aetiological role and predictive performance of protein biomarkers on incident CHD in individuals with and without T2D. Methods The discovery cohort included 1492 participants from the Cooperative Health Research in the Region of Augsburg (KORA) S4 study with 147 incident CHD cases (45 vs. 102 cases in the group with T2D and without T2D, respectively) during 15.6 years of follow-up. The validation cohort included 888 participants from the KORA-Age1 study with 70 incident CHD cases (19 vs. 51 cases in the group with T2D and without T2D, respectively) during 6.9 years of follow-up. We measured 233 plasma proteins related to cardiovascular disease and inflammation using proximity extension assay technology. Associations of proteins with incident CHD were assessed using Cox regression and Mendelian randomization (MR) analysis. Predictive models were developed using priority-Lasso and were evaluated on top of Framingham risk score variables using the C-index, category-free net reclassification index (cfNRI), and relative integrated discrimination improvement (IDI). Results We identified two proteins associated with incident CHD in individuals with and 29 in those without baseline T2D, respectively. Six of these proteins are novel candidates for incident CHD. MR suggested a potential causal role for hepatocyte growth factor in CHD development. The developed four-protein-enriched model for individuals with baseline T2D (ΔC-index: 0.017; cfNRI: 0.253; IDI: 0.051) and the 12-protein-enriched model for individuals without baseline T2D (ΔC-index: 0.054; cfNRI: 0.462; IDI: 0.024) consistently improved CHD prediction in the discovery cohort, while in the validation cohort, significant improvements were only observed for selected performance measures (with T2D: cfNRI: 0.633; without T2D: ΔC-index: 0.038; cfNRI: 0.465). Conclusions This study identified novel protein biomarkers associated with incident CHD in individuals with and without T2D and reaffirmed previously reported protein candidates. These findings enhance our understanding of CHD pathophysiology and provide potential targets for prevention and treatment.

Abstract Background Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with inflammation-related traits. The effect of PUFAs on health outcomes might be mediated by DNA methylation (DNAm). The aim of our study is to identify the impact of PUFA intake on DNAm in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and the Leiden Longevity Study (LLS). Results DNA methylation levels were measured in whole blood from the population-based KORA FF4 study (N = 1354) and LLS (N = 448), using the Illumina MethylationEPIC BeadChip and Illumina HumanMethylation450 array, respectively. We assessed associations between DNAm and intake of eight and four PUFAs in KORA and LLS, respectively. Where possible, results were meta-analyzed. Below the Bonferroni correction threshold (p

Abstract Background The COVID-19 pandemic restrictions posed challenges to maintaining healthy lifestyles and physical well-being. During the first mobility restrictions from March to mid-July 2020, the German population was advised to stay home, except for work, exercise, and essential shopping. Our objective was to comprehensively assess the impact of these restrictions on changes in physical activity and sedentary behavior to identify the most affected groups. Methods Between April 30, 2020, and May 12, 2020, we distributed a COVID-19-specific questionnaire to participants of the German National Cohort (NAKO). This questionnaire gathered information about participants’ physical activity and sedentary behavior currently compared to the time before the restrictions. We integrated this new data with existing information on anxiety, depressive symptoms, and physical activity. The analyses focused on sociodemographic factors, social relationships, physical health, and working conditions. Results Out of 152,421 respondents, a significant proportion reported altered physical activity and sedentary behavioral patterns due to COVID-19 restrictions. Over a third of the participants initially meeting the WHO’s physical activity recommendation could no longer meet the guidelines during the restrictions. Participants reported substantial declines in sports activities (mean change (M) = -0.38; 95% CI: -.390; -.378; range from -2 to + 2) and reduced active transportation (M = -0.12; 95% CI: -.126; -.117). However, they also increased recreational physical activities (M = 0.12; 95% CI: .117; .126) while engaging in more sedentary behavior (M = 0.24; 95% CI: .240; .247) compared to pre-restriction levels. Multivariable linear and log-binomial regression models indicated that younger adults were more affected by the restrictions than older adults. The shift to remote work, self-rated health, and depressive symptoms were the factors most strongly associated with changes in all physical activity domains, including sedentary behavior, and the likelihood to continue following the physical activity guidelines. Conclusions Mobility patterns shifted towards inactivity or low-intensity activities during the nationwide restrictions in the spring of 2020, potentially leading to considerable and lasting health risks.

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Summary: Background: High temperatures have been associated with increased mortality, with evidence reported predominately in large cities and for total cardiovascular or respiratory deaths. This case-crossover study examined heat-related cause-specific cardiopulmonary mortality and vulnerability factors using small-area data from Germany. Methods: We analyzed daily counts of cause-specific cardiopulmonary deaths from 380 German districts (2000–2016) and daily mean temperatures estimated by spatial–temporal models. We applied conditional quasi-Poisson regression using distributed lag nonlinear models to examine heat effects during May–September in each district and random-effects meta-analysis to pool the district-specific estimates. Potential individual- and district-level vulnerability factors were examined by subgroup analyses and meta-regressions, respectively. Findings: Heat was associated with increased mortality risks for all cardiopulmonary sub-causes. The relative risk (RR) of total cardiovascular and respiratory mortality for a temperature increment from the 75th to the 99th percentile was 1.24 (95% confidence interval: 1.23, 1.26) and 1.34 (1.30, 1.38), respectively. The RRs of cardiovascular sub-causes ranged from 1.16 (1.13, 1.19) for myocardial infarction to 1.32 (1.29, 1.36) for heart failure. For respiratory sub-causes, the RR was 1.27 (1.22, 1.31) for COPD and 1.49 (1.42, 1.57) for pneumonia. We observed greater susceptibility related to several individual- and district-level characteristics, e.g., among females or in highly urbanized districts. Heat vulnerability factors remained consistent between urban and rural areas. Interpretation: Our study highlights heat-related increases in cause-specific cardiopulmonary mortality across Germany and identifies key vulnerability factors, offering insights for improving public health practices to mitigate heat-related health impacts. Funding: European Union's Horizon 2020 research and innovation program; Helmholtz Associations Initiative and Networking Fund.

Objective: To determine the association between personality characteristics and use of different cancer screenings. Methods: We used data from the German National Cohort (NAKO; mean age was 53.0 years (SD: 9.2 years)) – a population-based cohort study. A total of 132,298 individuals were included in the analyses. As outcome measures, we used (self-reported): stool examination for blood (haemoccult test, early detection of bowel cancer), colonoscopy (screening for colorectal cancer), skin examination for moles (early detection of skin cancer), breast palpation by a doctor (early detection of breast cancer), x-ray examination of the breast (“mammography”, early detection of breast cancer), cervical smear test, finger examination of the rectum (early detection of prostate cancer), and blood test for prostate cancer (determination of Prostate-Specific Antigen level). The established Big Five Inventory-SOEP was used to quantify personality factors. It was adjusted for several covariates based on the Andersen model. Unadjusted and adjusted multiple logistic regressions were computed. Results: A higher probability of having a skin examination for moles, for example, was associated with a higher conscientiousness (OR: 1.07, p

COVID-19 lockdowns reduced nitrogen dioxide (NO2) and fine particulate matter (PM2.5) emissions in many countries. We aim to quantify the changes in these pollutants and to assess the attributable changes in mortality in Jiangsu, China; California, U.S.; Central-southern Italy; and Germany during COVID-19 lockdowns in early 2020. Accounting for meteorological impacts and air pollution time trends, we use a machine learning-based meteorological normalization technique and the difference-in-differences approach to quantify the changes in NO2 and PM2.5 concentrations due to lockdowns. Using region-specific estimates of the association between air pollution and mortality derived from a causal modeling approach using data from 2015 to 2019, we assess the changes in mortality attributable to the air pollution changes caused by the lockdowns in early 2020. During the lockdowns, NO2 reductions avoided 1.41 (95% empirical confidence interval [eCI]: 0.94, 1.88), 0.44 (95% eCI: 0.17, 0.71), and 4.66 (95% eCI: 2.03, 7.44) deaths per 100,000 people in Jiangsu, China; California, U.S.; and Central-southern Italy, respectively. Mortality benefits attributable to PM2.5 reductions were also significant, albeit of a smaller magnitude. For Germany, the mortality benefits attributable to NO2 changes were not significant (0.11; 95% eCI: −0.03, 0.25), and an increase in PM2.5 concentrations was associated with an increase in mortality of 0.35 (95% eCI: 0.22, 0.48) deaths per 100,000 people during the lockdown. COVID-19 lockdowns overall improved air quality and brought attributable health benefits, especially associated with NO2 improvements, with notable heterogeneity across regions. This study underscores the importance of accounting for local characteristics when policymakers adapt successful emission control strategies from other regions.

Introduction Circulating omentin levels have been positively associated with insulin sensitivity. Although a role for adiponectin in this relationship has been suggested, underlying mechanisms remain elusive. In order to reveal the relationship between omentin and systemic metabolism, this study aimed to investigate associations of serum concentrations of omentin and metabolites.Research design and methods This study is based on 1124 participants aged 61–82 years from the population-based KORA (Cooperative Health Research in the Region of Augsburg) F4 Study, for whom both serum omentin levels and metabolite concentration profiles were available. Associations were assessed with five multivariable regression models, which were stepwise adjusted for multiple potential confounders, including age, sex, body mass index, waist-to-hip ratio, lifestyle markers (physical activity, smoking behavior and alcohol consumption), serum adiponectin levels, high-density lipoprotein cholesterol, use of lipid-lowering or anti-inflammatory medication, history of myocardial infarction and stroke, homeostasis model assessment 2 of insulin resistance, diabetes status, and use of oral glucose-lowering medication and insulin.Results Omentin levels significantly associated with multiple metabolites including amino acids, acylcarnitines, and lipids (eg, sphingomyelins and phosphatidylcholines (PCs)). Positive associations for several PCs, such as diacyl (PC aa C32:1) and alkyl-alkyl (PC ae C32:2), were significant in models 1–4, whereas those with hydroxytetradecenoylcarnitine (C14:1-OH) were significant in all five models. Omentin concentrations were negatively associated with several metabolite ratios, such as the valine-to-PC ae C32:2 and the serine-to-PC ae C32:2 ratios in most models.Conclusions Our results suggest that omentin may influence insulin sensitivity and diabetes risk by changing systemic lipid metabolism, but further mechanistic studies investigating effects of omentin on metabolism of insulin-sensitive tissues are needed.

Objective: Measurements utilizing commercially available sets of reagents for determination of steroid hormone profiles by liquid chromatography–tandem mass spectrometry (LC-MS/MS) have become increasingly important for routine laboratories. However, method-specific publications of reference intervals obtained from sufficiently large studies are often missing. Methods: After validation of performance characteristics, a widely available kit for steroid analysis by LC-MS/MS was used to measure concentrations of 15 endogenous steroids (aldosterone, cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate, estradiol, testosterone, androstenedione, dihydrotestosterone, dehydroepiandrosterone, 17-hydroxyprogesterone, 11-deoxycorticosterone, progesterone) in more than 500 blood samples from a population-based study. While randomly selected from a larger cohort, the samples equally represented both sexes and covered a wide range of adult age groups. Age- and sex-specific reference intervals were calculated, and correlation with BMI was assessed. Results: Performance characteristics of the assay matched expectations for 9 of 15 steroids. For most of them, reference intervals obtained from our study population were comparable to those reported by others, with age and sex being the major determinants. A sex-specific correlation with BMI was found for seven steroids. We identified limitations regarding sensitivity of the method for quantification of progesterone in males and postmenopausal females. Concentrations of aldosterone, 21-deoxycortisol, estradiol, 11-deoxycorticosterone, and dihydrotestosterone could not be quantified in a large percentage of samples. Conclusions: The reference intervals for nine steroids will support meaningful interpretation for steroid profiles as measured by a widely used kit for LC-MS/MS-based quantification. Laboratories using such kits must be aware of potential limitations in sensitivity for some steroids included in the profile. Significance Statement Quantification of steroid hormones is a cornerstone for diagnosis of several diseases. Commonly used immunoassays have limitations in specificity. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) is a promising alternative, particularly if methods are harmonized across laboratories. The use of kits from commercial suppliers might support this. Clinical interpretation of steroid concentrations requires availability of appropriate reference intervals (RIs), but studies on RIs reported in the literature differ in preanalytical and analytical procedures. Here, we provide RIs for steroids measured by a widely available kit under preanalytical conditions mirroring common clinical practice. Such RIs might facilitate interpretation for those using the same method and comparable conditions in clinical routine.

Abstract Metadata from epidemiological studies, including chronic disease outcome metadata (CDOM), are important to be findable to allow interpretability and reusability. We propose a comprehensive metadata schema and used it to assess public availability and findability of CDOM from German population-based observational studies participating in the consortium National Research Data Infrastructure for Personal Health Data (NFDI4Health). Additionally, principal investigators from the included studies completed a checklist evaluating consistency with FAIR principles (Findability, Accessibility, Interoperability, Reusability) within their studies. Overall, six of sixteen studies had complete publicly available CDOM. The most frequent CDOM source was scientific publications and the most frequently missing metadata were availability of codes of the International Classification of Diseases, Tenth Revision (ICD-10). Principal investigators’ main perceived barriers for consistency with FAIR principles were limited human and financial resources. Our results reveal that CDOM from German population-based studies have incomplete availability and limited findability. There is a need to make CDOM publicly available in searchable platforms or metadata catalogues to improve their FAIRness, which requires human and financial resources.

Abstract Lyme borreliosis (LB) is caused by the transmission of Borrelia burgdorferi s.l. from ticks to humans. Climate affects tick abundance, and climate change is projected to promote shifts in abundance in Europe, potentially increasing human exposure. We analyzed serum samples collected between the years 2014–2019 from German National Cohort (NAKO) participants at four study sites (Augsburg, Berlin, Hanover, Münster) for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using an enzyme‐linked immunosorbent assay (ELISA) and line blot immunoassay as confirmatory test for positive and equivocal ELISA samples. We reported crude and weighted seropositivity proportions for local estimates. We used mixed model analysis to investigate associated factors, such as age, sex, migration background, or animal contacts. We determined the serostatus of 14,207 participants. The weighted seropositivity proportions were 3.4% (IgG) and 0.4% (IgM) in Augsburg, 4.1% (IgG) and 0.6% (IgM) in northern Berlin, 3.0% (IgG) and 0.9% (IgM) in Hanover, and 2.7% (IgG) and 0.6% (IgM) in Münster. We found higher odds for IgG seropositivity with advancing age (p

Abstract Background B vitamins such as folate (B9), B6, and B12 are key in one carbon metabolism, which generates methyl donors for DNA methylation. Several studies have linked differential methylation to self-reported intakes of folate and B12, but these estimates can be imprecise, while metabolomic biomarkers can offer an objective assessment of dietary intakes. We explored blood metabolomic biomarkers of folate and vitamins B6 and B12, to carry out epigenome-wide analyses across up to three European cohorts. Associations between self-reported habitual daily B vitamin intakes and 756 metabolites (Metabolon Inc.) were assessed in serum samples from 1064 UK participants from the TwinsUK cohort. The identified B vitamin metabolomic biomarkers were then used in epigenome-wide association tests with fasting blood DNA methylation levels at 430,768 sites from the Infinium HumanMethylation450 BeadChip in blood samples from 2182 European participants from the TwinsUK and KORA cohorts. Candidate signals were explored for metabolite associations with gene expression levels in a subset of the TwinsUK sample (n = 297). Metabolomic biomarker epigenetic associations were also compared with epigenetic associations of self-reported habitual B vitamin intakes in samples from 2294 European participants. Results Eighteen metabolites were associated with B vitamin intakes after correction for multiple testing (Bonferroni-adj. p

Summary: Background: The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, respectively, have not been provided. Methods: MG, GO and 3-DG were measured by LC-MS in 1304 serum samples of two populations (KORA, n = 482; BiDirect, n = 822) and assessed for associations with genome-wide SNPs (GWAS) and with phenome-wide traits. Redundancy analysis (RDA) was used to identify major independent trait associations. Findings: Mutual correlations of dicarbonyls were highly significant, being stronger between MG and GO (ρ = 0.6) than between 3-DG and MG or GO (ρ = 0.4). Significant phenotypic results included associations of all dicarbonyls with sex, waist-to-hip ratio, glomerular filtration rate (GFR), gamma-glutamyltransferase (GGT), and hypertension, of MG and GO with age and C-reactive protein, of GO and 3-DG with glucose and antidiabetics, of MG with contraceptives, of GO with ferritin, and of 3-DG with smoking. RDA revealed GFR, GGT and, in case of 3-DG, glucose as major contributors to dicarbonyl variance. GWAS did not identify genome-wide significant loci. SNPs previously associated with glyoxalase activity did not reach nominal significance. When multiple testing was restricted to the lead SNPs of GWASs on the traits selected by RDA, 3-DG was found to be associated (p = 2.3 × 10−5) with rs1741177, an eQTL of NF-κB inhibitor NFKBIA. Interpretation: This large-scale, population-based study has identified numerous associations, with GFR and GGT being of pivotal importance, providing unbiased perspectives on dicarbonyls beyond the current state. Funding: Deutsche Forschungsgemeinschaft, Helmholtz Munich, German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF).

BackgroundMultiple risk factors contribute jointly to the development and progression of cardiometabolic diseases. Therefore, joint longitudinal trajectories of multiple risk factors might represent different degrees of cardiometabolic risk.MethodsWe analyzed population-based data comprising three examinations (Exam 1: 1999-2001, Exam 2: 2006-2008, Exam 3: 2013-2014) of 976 male and 1004 female participants of the KORA cohort (Southern Germany). Participants were followed up for cardiometabolic diseases, including cardiovascular mortality, myocardial infarction and stroke, or a diagnosis of type 2 diabetes, until 2016. Longitudinal multivariate k-means clustering identified sex-specific trajectory clusters based on nine cardiometabolic risk factors (age, systolic and diastolic blood pressure, body-mass-index, waist circumference, Hemoglobin-A1c, total cholesterol, high- and low-density lipoprotein cholesterol). Associations between clusters and cardiometabolic events were assessed by logistic regression models.ResultsWe identified three trajectory clusters for men and women, respectively. Trajectory clusters reflected a distinct distribution of cardiometabolic risk burden and were associated with prevalent cardiometabolic disease at Exam 3 (men: odds ratio (OR)ClusterII = 2.0, 95% confidence interval: (0.9-4.5); ORClusterIII = 10.5 (4.8-22.9); women: ORClusterII = 1.7 (0.6-4.7); ORClusterIII = 5.8 (2.6-12.9)). Trajectory clusters were furthermore associated with incident cardiometabolic cases after Exam 3 (men: ORClusterII = 3.5 (1.1-15.6); ORClusterIII = 7.5 (2.4-32.7); women: ORClusterII = 5.0 (1.1-34.1); ORClusterIII = 8.0 (2.2-51.7)). Associations remained significant after adjusting for a single time point cardiovascular risk score (Framingham).ConclusionsOn a population-based level, distinct longitudinal risk profiles over a 14-year time period are differentially associated with cardiometabolic events. Our results suggest that longitudinal data may provide additional information beyond single time-point measures. Their inclusion in cardiometabolic risk assessment might improve early identification of individuals at risk.

BackgroundThe objective of this study was to investigate the differences in presenting symptoms between patients with and without diabetes being diagnosed with an acute myocardial infarction (AMI).MethodsA total of 5,900 patients with a first-time AMI were included into the analysis. All patients aged between 25 and 84 years were recorded by the population-based Myocardial Infarction Registry in Augsburg, Germany, between 2010 and 2017. The presence (yes/no) of 12 AMI typical symptoms during the acute event was assessed within the scope of a face-to-face interview. Multivariable adjusted logistic regression models were calculated to analyze the associations between presenting symptoms and diabetes mellitus in AMI patients.ResultsPatients with diabetes had significantly less frequent typical pain symptoms, including typical chest pain. Also, other symptoms like sweating, vomiting/nausea, dizziness/vertigo and fear of death/feeling of annihilation occurred significantly more likely in non-diabetic patients. The only exception was the symptom of shortness of breath, which was found significantly more often in patients with diabetes. In multivariable-adjusted regression models, however, the observed effects were attenuated. In patients younger than 55 years, the associations between diabetes and various symptoms were mainly missing.ConclusionsType 2 diabetes mellitus is a risk factor not only for the development of AMI, but is also associated with an adverse outcome after AMI. Atypical clinical presentation additionally complicates the diagnostic process. It is therefore essential for physicians to be aware of the more often atypical symptoms that diabetic AMI patients report.

IntroductionChanges in DNA methylation can increase or suppress the expression of health-relevant genes. We investigated for the first time the relationship between habitual food consumption and changes in DNA methylation.MethodsThe German KORA FF4 and KORA Fit studies were used to study the change in methylation over a median follow-up of 4 years. Only subjects participating in both surveys and with available dietary and methylation data were included in the analysis (n = 465). DNA methylation was measured using the Infinium MethylationEPIC BeadChip (Illumina), resulting in 735,527 shared CpGs across both studies. Generalized estimating equation models with an interaction term of exposure and time point were used to analyze the association of 34 food groups, folic acid, and two dietary patterns with changes in DNA methylation over time.ResultsThe results were corrected for genomic inflation. Significant interaction terms indicate different effects between both time points. We observed only a few significant associations between food intake and change in DNA methylation, except for cream and spirit consumption. The annotated genes include CLN3, PROM1, DLEU7, TLL2, and UGT1A10.DiscussionWe identified weak associations between food consumption and DNA methylation change. The differential results for cream and spirits, both consumed in low quantities, require replication in independent studies.

Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Abstract Background Due to the asymptomatic nature of the early stages, chronic kidney disease (CKD) is usually diagnosed at late stages and lacks targeted therapy, highlighting the need for new biomarkers to better understand its pathophysiology and to be used for early diagnosis and therapeutic targets. Given the close relationship between CKD and cardiovascular disease (CVD), we investigated the associations of 233 CVD- and inflammation-related plasma proteins with kidney function decline and aimed to assess whether the observed associations are causal. Methods We included 1140 participants, aged 55–74 years at baseline, from the Cooperative Health Research in the Region of Augsburg (KORA) cohort study, with a median follow-up time of 13.4 years and 2 follow-up visits. We measured 233 plasma proteins using a proximity extension assay at baseline. In the discovery analysis, linear regression models were used to estimate the associations of 233 proteins with the annual rate of change in creatinine-based estimated glomerular filtration rate (eGFRcr). We further investigated the association of eGFRcr-associated proteins with the annual rate of change in cystatin C-based eGFR (eGFRcys) and eGFRcr-based incident CKD. Two-sample Mendelian randomization was used to infer causality. Results In the fully adjusted model, 66 out of 233 proteins were inversely associated with the annual rate of change in eGFRcr, indicating that higher baseline protein levels were associated with faster eGFRcr decline. Among these 66 proteins, 21 proteins were associated with both the annual rate of change in eGFRcys and incident CKD. Mendelian randomization analyses on these 21 proteins suggest a potential causal association of higher tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) level with eGFR decline. Conclusions We reported 21 proteins associated with kidney function decline and incident CKD and provided preliminary evidence suggesting a potential causal association between TNFRSF11A and kidney function decline. Further Mendelian randomization studies are needed to establish a conclusive causal association.

Despite extensive research on 5-methylcytosine (5mC) in relation to smoking, there has been limited exploration into the interaction between smoking and 5-hydroxymethylcytosine (5hmC). In this study, total DNA methylation (5mC+5hmC), true DNA methylation (5mC) and hydroxymethylation (5hmC) levels were profiled utilizing conventional bisulphite (BS) and oxidative bisulphite (oxBS) treatment, measured with the Illumina Infinium Methylation EPIC BeadChip. An epigenome-wide association study (EWAS) of 5mC+5hmC methylation revealed a total of 38,575 differentially methylated positions (DMPs) and 2023 differentially methylated regions (DMRs) associated with current smoking, along with 82 DMPs and 76 DMRs associated with former smoking (FDR-adjusted p < 0.05). Additionally, a focused examination of 5mC identified 33 DMPs linked to current smoking and 1 DMP associated with former smoking (FDR-adjusted p < 0.05). In the 5hmC category, eight DMPs related to current smoking and two DMPs tied to former smoking were identified, each meeting a suggestive threshold (p < 1 × 10−5). The substantial number of recognized DMPs, including 5mC+5hmC (7069/38,575, 2/82), 5mC (0/33, 1/1), and 5hmC (2/8, 0/2), have not been previously reported. Our findings corroborated previously established methylation positions and revealed novel candidates linked to tobacco smoking. Moreover, the identification of hydroxymethylated CpG sites with suggestive links provides avenues for future research.

Accurate risk prediction for myocardial infarction (MI) is crucial for preventive strategies, given its significant impact on global mortality and morbidity. Here, we propose a novel deep-learning approach to enhance the prediction of incident MI cases by incorporating metabolomics alongside clinical risk factors. We utilized data from the KORA cohort, including the baseline S4 and follow-up F4 studies, consisting of 1454 participants without prior history of MI. The dataset comprised 19 clinical variables and 363 metabolites. Due to the imbalanced nature of the dataset (78 observed MI cases and 1376 non-MI individuals), we employed a generative adversarial network (GAN) model to generate new incident cases, augmenting the dataset and improving feature representation. To predict MI, we further utilized multi-layer perceptron (MLP) models in conjunction with the synthetic minority oversampling technique (SMOTE) and edited nearest neighbor (ENN) methods to address overfitting and underfitting issues, particularly when dealing with imbalanced datasets. To enhance prediction accuracy, we propose a novel GAN for feature-enhanced (GFE) loss function. The GFE loss function resulted in an approximate 2% improvement in prediction accuracy, yielding a final accuracy of 70%. Furthermore, we evaluated the contribution of each clinical variable and metabolite to the predictive model and identified the 10 most significant variables, including glucose tolerance, sex, and physical activity. This is the first study to construct a deep-learning approach for producing 7-year MI predictions using the newly proposed loss function. Our findings demonstrate the promising potential of our technique in identifying novel biomarkers for MI prediction.

Abstract Background Metabolic Syndrome (MetS) is characterized by risk factors such as abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension, and hyperglycemia, which contribute to the development of cardiovascular disease and type 2 diabetes. Here, we aim to identify candidate metabolite biomarkers of MetS and its associated risk factors to better understand the complex interplay of underlying signaling pathways. Methods We quantified serum samples of the KORA F4 study participants (N = 2815) and analyzed 121 metabolites. Multiple regression models adjusted for clinical and lifestyle covariates were used to identify metabolites that were Bonferroni significantly associated with MetS. These findings were replicated in the SHIP-TREND-0 study (N = 988) and further analyzed for the association of replicated metabolites with the five components of MetS. Database-driven networks of the identified metabolites and their interacting enzymes were also constructed. Results We identified and replicated 56 MetS-specific metabolites: 13 were positively associated (e.g., Val, Leu/Ile, Phe, and Tyr), and 43 were negatively associated (e.g., Gly, Ser, and 40 lipids). Moreover, the majority (89%) and minority (23%) of MetS-specific metabolites were associated with low HDL-C and hypertension, respectively. One lipid, lysoPC a C18:2, was negatively associated with MetS and all of its five components, indicating that individuals with MetS and each of the risk factors had lower concentrations of lysoPC a C18:2 compared to corresponding controls. Our metabolic networks elucidated these observations by revealing impaired catabolism of branched-chain and aromatic amino acids, as well as accelerated Gly catabolism. Conclusion Our identified candidate metabolite biomarkers are associated with the pathophysiology of MetS and its risk factors. They could facilitate the development of therapeutic strategies to prevent type 2 diabetes and cardiovascular disease. For instance, elevated levels of lysoPC a C18:2 may protect MetS and its five risk components. More in-depth studies are necessary to determine the mechanism of key metabolites in the MetS pathophysiology.

Abstract Obesity is characterized by the accumulation of adipose tissue in different body compartments. Whether adipose tissue directly affects kidney function is still unknown. We aimed to investigate the role of the adipose tissue and circulating creatinine, cystatin C and kidney function in subjects free of cardio-renal diseases. In the KORA-MRI population-based study, 377 subjects (mean age 56.2 ± 9.2 years; 41.6% female) underwent whole-body 3T-MRI examination. Adipose tissue defined as visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were quantified from T1-DIXON sequence using a semi-automatic algorithm. Serum creatinine and cystatin C were measured using standard laboratory and estimated glomerular filtration rate (e-GFR) was performed based on creatinine (e-GFRcrea), cystatin C (e-GFRcys) and creatinine-cystatin C (e-GFRcc). Linear regression analysis, adjusted for risk factors, was used to investigate the relationship between adipose tissue and circulating creatinine, cystatin C, and kidney function. In multivariate analyses VAT was inversely associated with eGFRcys (ß = − 4.88, p = 30. VAT is positively associated with serum cystatin C and inversely with eGFR based on cystatin C, suggesting a direct involvement of visceral adipose tissue in increased metabolism of cystatin C and consequently decreased kidney function.

Abstract Background Intervertebral disc degeneration (IVDD) may be linked to dysregulations of skeletal muscle glucose metabolism and fatty alterations of muscle composition (Myosteatosis). Our aim was to evaluate the different associations of magnetic resonance imaging (MRI)‐based paravertebral myosteatosis with lumbar disc degeneration in individuals with impaired glucose metabolism and normoglycaemic controls. Methods In total, 304 individuals (mean age: 56.3 ± 9.1 years, 53.6% male sex, mean body mass index [BMI]: 27.6 ± 4.7 kg/m2) from a population‐based cohort study who underwent 3‐Tesla whole‐body chemical‐shift‐encoded (six echo times) and T2‐weighted single‐shot‐fast‐spin‐echo MRI were included. Lumbar disc degeneration was assessed at motion segments L1 to L5, categorized according to the Pfirrmann score and defined as Pfirrmann grade > 2 and/or disc bulging/herniation on at least one segment. Fat content of the autochthonous back muscles and the quadratus lumborum muscle was quantified as proton density fat fraction (PDFFmuscle). Logistic regression models adjusted for age, sex, BMI and regular physical activity were calculated to evaluate the association between PDFFmuscle and outcome IVDD. Results The overall prevalence of IVDD was 79.6%. There was no significant difference in the prevalence or severity distribution of IVDD between participants with or without impaired glucose metabolism (77.7% vs. 80.7%, P = 0.63 and P = 0.71, respectively). PDFFmuscle was significantly and positively associated with an increased risk for the presence of IVDD in participants with impaired glycaemia when adjusted for age, sex and BMI (PDFFautochthonous back muscles: odds ratio [OR] 2.16, 95% confidence interval [CI] [1.09, 4.3], P = 0.03; PDFFquadratus lumborum: OR 2.01, 95% CI [1.04, 3.85], P = 0.04). After further adjustment for regular physical activity, the results attenuated, albeit approaching statistical significance (PDFFautochthonous back muscles: OR 1.97, 95% CI [0.97, 3.99], P = 0.06; PDFFquadratus lumborum: OR 1.86, 95% CI [0.92, 3.76], P = 0.09). No significant associations were shown in healthy controls (PDFFautochthonous back muscles: OR 0.62, 95% CI [0.34, 1.14], P = 0.13; PDFFquadratus lumborum: OR 1.06, 95% CI [0.6, 1.89], P = 0.83). Conclusions Paravertebral myosteatosis is positively associated with intervertebral disc disease in individuals with impaired glucose metabolism, independent of age, sex and BMI. Regular physical activity may confound these associations. Longitudinal studies will help to better understand the pathophysiological role of skeletal muscle in those with concomitant disturbed glucose haemostasis and intervertebral disc disease, as well as possible underlying causal relationships.

Abstract Background Polygenic scores (PGSs) combining genetic variants found to be associated with creatinine-based estimated glomerular filtration rate (eGFRcrea) have been applied in various study populations with different age ranges. This has shown that PGS explain less eGFRcrea variance in the elderly. Our aim was to understand how differences in eGFR variance and the percentage explained by PGS varies between population of general adults and elderly. Results We derived a PGS for cystatin-based eGFR (eGFRcys) from published genome-wide association studies. We used the 634 variants known for eGFRcrea and the 204 variants identified for eGFRcys to calculate the PGS in two comparable studies capturing a general adult and an elderly population, KORA S4 (n = 2,900; age 24–69 years) and AugUR (n = 2,272, age ≥ 70 years). To identify potential factors determining age-dependent differences on the PGS-explained variance, we evaluated the PGS variance, the eGFR variance, and the beta estimates of PGS association on eGFR. Specifically, we compared frequencies of eGFR-lowering alleles between general adult and elderly individuals and analyzed the influence of comorbidities and medication intake. The PGS for eGFRcrea explained almost twice as much (R2 = 9.6%) of age-/sex adjusted eGFR variance in the general adults compared to the elderly (4.6%). This difference was less pronounced for the PGS for eGFRcys (4.7% or 3.6%, respectively). The beta-estimate of the PGS on eGFRcrea was higher in the general adults compared to the elderly, but similar for the PGS on eGFRcys. The eGFR variance in the elderly was reduced by accounting for comorbidities and medication intake, but this did not explain the difference in R2-values. Allele frequencies between general adult and elderly individuals showed no significant differences except for one variant near APOE (rs429358). We found no enrichment of eGFR-protective alleles in the elderly compared to general adults. Conclusions We concluded that the difference in explained variance by PGS was due to the higher age- and sex-adjusted eGFR variance in the elderly and, for eGFRcrea, also by a lower PGS association beta-estimate. Our results provide little evidence for survival or selection bias.

Background: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. Methods: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. Results: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. Conclusions: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

BackgroundTaxes on sugar-sweetened beverages (SSBs) have been implemented globally to reduce the burden of cardiometabolic diseases by disincentivizing consumption through increased prices (e.g., 1 peso/litre tax in Mexico) or incentivizing industry reformulation to reduce SSB sugar content (e.g., tiered structure of the United Kingdom [UK] Soft Drinks Industry Levy [SDIL]). In Germany, where no tax on SSBs is enacted, the health and economic impact of SSB taxation using the experience from internationally implemented tax designs has not been evaluated. The objective of this study was to estimate the health and economic impact of national SSBs taxation scenarios in Germany.Methods and findingsIn this modelling study, we evaluated a 20% ad valorem SSB tax with/without taxation of fruit juice (based on implemented SSB taxes and recommendations) and a tiered tax (based on the UK SDIL) in the German adult population aged 30 to 90 years from 2023 to 2043. We developed a microsimulation model (IMPACTNCD Germany) that captures the demographics, risk factor profile and epidemiology of type 2 diabetes, coronary heart disease (CHD) and stroke in the German population using the best available evidence and national data. For each scenario, we estimated changes in sugar consumption and associated weight change. Resulting cases of cardiometabolic disease prevented/postponed and related quality-adjusted life years (QALYs) and economic impacts from healthcare (medical costs) and societal (medical, patient time, and productivity costs) perspectives were estimated using national cost and health utility data. Additionally, we assessed structural uncertainty regarding direct, body mass index (BMI)-independent cardiometabolic effects of SSBs and cross-validated results with an independently developed cohort model (PRIMEtime). We found that SSB taxation could reduce sugar intake in the German adult population by 1 g/day (95%-uncertainty interval [0.05, 1.65]) for a 20% ad valorem tax on SSBs leading to reduced consumption through increased prices (pass-through of 82%) and 2.34 g/day (95%-UI [2.32, 2.36]) for a tiered tax on SSBs leading to 30% reduction in SSB sugar content via reformulation. Through reductions in obesity, type 2 diabetes, and cardiovascular disease (CVD), 106,000 (95%-UI [57,200, 153,200]) QALYs could be gained with a 20% ad valorem tax and 192,300 (95%-UI [130,100, 254,200]) QALYs with a tiered tax. Respectively, €9.6 billion (95%-UI [4.7, 15.3]) and €16.0 billion (95%-UI [8.1, 25.5]) costs could be saved from a societal perspective over 20 years. Impacts of the 20% ad valorem tax were larger when additionally taxing fruit juice (252,400 QALYs gained, 95%-UI [176,700, 325,800]; €11.8 billion costs saved, 95%-UI [€6.7, €17.9]), but impacts of all scenarios were reduced when excluding direct health effects of SSBs. Cross-validation with PRIMEtime showed similar results. Limitations include remaining uncertainties in the economic and epidemiological evidence and a lack of product-level data.ConclusionsIn this study, we found that SSB taxation in Germany could help to reduce the national burden of noncommunicable diseases and save a substantial amount of societal costs. A tiered tax designed to incentivize reformulation of SSBs towards less sugar might have a larger population-level health and economic impact than an ad valorem tax that incentivizes consumer behaviour change only through increased prices.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

BackgroundSex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses.MethodsThe observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies.ResultsIn the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value

Abstract The availability of polygenic scores for type 2 diabetes (T2D) raises the question, whether assessing family history might become redundant. However, family history not only involves shared genetics, but also shared environment. It was the aim of this study to assess the independent and combined effects of one family risk score (FamRS) and a polygenic score (PGS) on prevalent and incident T2D risk in a population-based study from Germany (n = 3071). The study was conducted in 2004/2005 with up to 12 years of follow-up. The FamRS takes into account not only the number of diseased first grade relatives, but also age at onset of the relatives and age of participants. 256 prevalent and additional 163 incident T2D cases were recorded. Prevalence of T2D increased sharply for those within the top quantile of the PGS distribution resulting in an OR of 19.16 (p

Blood coagulation is a complex physiological process critical for maintaining hemostasis, and disruptions in this system can lead to various health complications. Since the effects of specific food groups on a series of circulating coagulation parameters in the population are not well established, this study examines such associations in the population-based KORA-Fit study. A total of 595 subjects (263 men and 332 women) born between 1945 and 1964 and living in the study region of Augsburg were included in the study. Habitual food intake was estimated based on a combination of repeated 24-h food lists (24HFLs) and a food frequency questionnaire (FFQ). Antithrombin III, D-dimers, factor VIII, fibrinogen, protein C, protein S, aPTT, Quick value and INR were measured in citrate plasma. Multivariable linear regression models were applied to investigate associations between the consumption of specific foods of plant or animal origin and hemostatic factors. We found that the consumption of plant-based food groups, including green leafy vegetables (rich in vitamin K1), were hardly associated with coagulation parameters. Surprisingly, a high consumption of dairy products and especially butter were associated with higher D-dimer concentrations. These findings need further evaluation in prospective studies.

Background: Short-term associations between heat and cardiovascular disease (CVD) mortality have been examined mostly in large cities. However, different vulnerability and exposure levels may contribute to spatial heterogeneity. This study assessed heat effects on CVD mortality and potential vulnerability factors using data from three European countries, including urban and rural settings. Methods: We collected daily counts of CVD deaths aggregated at the small-area level in Norway (small-area level: municipality), England and Wales (lower super output areas), and Germany (district) during the warm season (May-September) from 1996 to 2018. Daily mean air temperatures estimated by spatial–temporal models were assigned to each small area. Within each country, we applied area-specific Quasi-Poisson regression using distributed lag nonlinear models to examine the heat effects at lag 0–1 days. The area-specific estimates were pooled by random-effects meta-analysis to derive country-specific and overall heat effects. We examined individual- and area-level heat vulnerability factors by subgroup analyses and meta-regression, respectively. Results: We included 2.84 million CVD deaths in analyses. For an increase in temperature from the 75th to the 99th percentile, the pooled relative risk (RR) for CVD mortality was 1.14 (95% CI: 1.03, 1.26), with the country-specific RRs ranging from 1.04 (1.00, 1.09) in Norway to 1.24 (1.23, 1.26) in Germany. Heat effects were stronger among women [RRs (95% CIs) for women and men: 1.18 (1.08, 1.28) vs. 1.12 (1.00, 1.24)]. Greater heat vulnerability was observed in areas with high population density, high degree of urbanization, low green coverage, and high levels of fine particulate matter. Conclusion: This study provides evidence for the heat effects on CVD mortality in European countries using high-resolution data from both urban and rural areas. Besides, we identified individual- and area-level heat vulnerability factors. Our findings may facilitate the development of heat-health action plans to increase resilience to climate change.

Introduction: The complex interplay of multiple environmental factors and cardiovascular has scarcely been studied. Within the EXPANSE project, we evaluated the association between long-term exposure to multiple environmental indices and stroke incidence across Europe. Methods: Participants from three traditional adult cohorts (Germany, Netherlands and Sweden) and four administrative cohorts (Catalonia [region Spain], Rome [city-wide], Greece and Sweden [nationwide]) were followed until incident stroke, death, migration, loss of follow-up or study end. We estimated exposures at residential addresses from different exposure domains: air pollution (nitrogen dioxide (NO2), particulate matter

BackgroundThe aim of this study was to investigate the association between inflammatory plasma protein concentrations and long-term mortality in patients with ST-elevation myocardial infarction (STEMI).MethodsFor 343 STEMI patients recorded between 2009 and 2013 by the population-based Myocardial Infarction Registry Augsburg, 92 inflammatory plasma proteins were measured at the index event using the OLINK inflammation panel. In multivariable-adjusted Cox regression models, the association between each plasma protein and all-cause long-term mortality was investigated. Median follow-up time was 7.6 (IQR: 2.4) years. For plasma protein that showed a strong association with long-term mortality, a 5-year survival ROC analysis was performed.ResultsOne plasma protein, namely Fibroblast Growth Factor 23 (FGF-23), was particularly well associated with long-term mortality in the multivariable-adjusted Cox model with an FDR-adjusted p-value of 0.05 in the multivariable-adjusted Cox models.ConclusionsFGF-23 is independently associated with long-term mortality after STEMI and might play an important role in the response to myocardial injury. The results suggest FGF-23 to be a useful marker in the long-term treatment of STEMI patients and a potential target for drug development.

Climate change poses a serious threat to human health worldwide, while aging populations increase. However, no study has ever investigated the effects of air temperature on epigenetic age acceleration. This study involved 1,725 and 1,877 participants from the population-based KORA F4 (2006–2008) and follow-up FF4 (2013–2014) studies, respectively, conducted in Augsburg, Germany. The difference between epigenetic age and chronological age was referred to as epigenetic age acceleration and reflected by Horvath’s epigenetic age acceleration (HorvathAA), Hannum’s epigenetic age acceleration (HannumAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and Epigenetic Skin and Blood Age acceleration (SkinBloodAA). Daily air temperature was estimated using hybrid spatiotemporal regression-based models. To explore the medium- and long-term effects of air temperature modeled in time and space on epigenetic age acceleration, we applied generalized estimating equations (GEE) with distributed lag non-linear models, and GEE, respectively. We found that high temperature exposure based on the 8-week moving average air temperature (97.5th percentile of temperature compared to median temperature) was associated with increased HorvathAA, HannumAA, GrimAA, and SkinBloodAA: 1.83 (95% CI: 0.29–3.37), 11.71 (95% CI: 8.91–14.50), 2.26 (95% CI: 1.03–3.50), and 5.02 (95% CI: 3.42–6.63) years, respectively. Additionally, we found consistent results with high temperature exposure based on the 4-week moving average air temperature was associated with increased HannumAA, GrimAA, and SkinBloodAA: 9.18 (95% CI: 6.60–11.76), 1.78 (95% CI: 0.66–2.90), and 4.07 (95% CI: 2.56–5.57) years, respectively. For the spatial variation in annual average temperature, a 1 °C increase was associated with an increase in all five measures of epigenetic age acceleration (HorvathAA: 0.41 [95% CI: 0.24–0.57], HannumAA: 2.24 [95% CI: 1.95–2.53], PhenoAA: 0.32 [95% CI: 0.05–0.60], GrimAA: 0.24 [95%: 0.11–0.37], and SkinBloodAA: 1.17 [95% CI: 1.00–1.35] years). In conclusion, our results provide first evidence that medium- and long-term exposures to high air temperature affect increases in epigenetic age acceleration.

Introduction: Numerous studies have shown associations between daily concentrations of fine particles (e.g., particulate matter with an aerodynamic diameter ≤2.5 µm; PM2.5) and morbidity. However, evidence for ultrafine particles (UFP; particles with an aerodynamic diameter of 10–100 nm) remains conflicting. Therefore, we aimed to examine the short-term associations of UFP with five cause-specific hospital admission endpoints for Leipzig, Dresden, and Augsburg, Germany. Material and methods: We obtained daily counts of (cause-specific) cardiorespiratory hospital admissions between 2010 and 2017. Daily average concentrations of UFP, total particle number (PNC; 10–800 nm), and black carbon (BC) were measured at six sites; PM2.5 and nitrogen dioxide (NO2) were obtained from monitoring networks. We assessed immediate (lag 0–1), delayed (lag 2–4, lag 5–7), and cumulative (lag 0–7) effects by applying station-specific confounder-adjusted Poisson regression models. We then used a novel multi-level meta-analytical method to obtain pooled risk estimates. Finally, we performed two-pollutant models to investigate interdependencies between pollutants and examined possible effect modification by age, sex, and season. Results: UFP showed a delayed (lag 2–4) increase in respiratory hospital admissions of 0.69% [95% confidence interval (CI): −0.28%; 1.67%]. For other hospital admission endpoints, we found only suggestive results. Larger particle size fractions, such as accumulation mode particles (particles with an aerodynamic diameter of 100–800 nm), generally showed stronger effects (respiratory hospital admissions & lag 2–4: 1.55% [95% CI: 0.86%; 2.25%]). PM2.5 showed the most consistent associations for (cardio-)respiratory hospital admissions, whereas NO2 did not show any associations. Two-pollutant models showed independent effects of PM2.5 and BC. Moreover, higher risks have been observed for children. Conclusions: We observed clear associations with PM2.5 but UFP or PNC did not show a clear association across different exposure windows and cause-specific hospital admissions. Further multi-center studies are needed using harmonized UFP measurements to draw definite conclusions on the health effects of UFP.