Search

Background: In magnetic resonance imaging (MRI), the comparability of gated and non-gated measurements of the left atrial (LA) area and function and their association with cardiovascular risk factors have not been firmly established. Methods: 3-Tesla MRIs were performed on 400 subjects enrolled in the KORA (Cooperative Health Research in the Augsburg Region) MRI study. The LA maximum and minimum sizes were segmented in gated CINE four-chamber sequences (LAmax and LAmin) and non-gated T1 VIBE-Dixon (NGLA). The area-based LA function was defined as LAaf = (LAmax − LAmin)/LAmax. Inter-and intra-reader reliability tests were performed (n = 31). Linear regression analyses were conducted to link LA size and function with cardiovascular risk factors. Results: Data from 378 subjects were included in the analysis (mean age: 56.3 years, 57.7 % male). The measurements were highly reproducible (all intraclass correlation coefficients ≥ 0.98). The average LAmax was 19.6 ± 4.5 cm2, LAmin 11.9 ± 3.5 cm2, NGLA 16.8 ± 4 cm2 and LAaf 40 ± 9%. In regression analysis, hypertension was significantly associated with larger gated LAmax (β = 1.30), LAmin (β = 1.07), and non-gated NGLA (β = 0.94, all p ≤ 0.037). Increasing age was inversely associated with LAaf (β = −1.93, p < 0.001). Conclusion: LA enlargement, as measured in gated and non-gated CMR is associated with hypertension, while the area-based LA function decreases with age.

The phase angle (PhA) measured with bioelectrical impedance analysis is considered to reflect the interrelated components body cell mass and fluid distribution based on technical and physical aspects of the PhA measurement. However, the biomedical meaning of the PhA remains vague. Previous studies mainly assessed associations of the PhA with numerous diseases and health outcomes, but few connected protein markers to the PhA. To broaden our understanding of the biomedical background of the PhA, we aimed to explore a proteomics profile associated with the PhA and related biological factors.The study sample encompassed 1484 participants (725 women and 759 men) aged 55-74 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 study. Proteomics measurements were performed with a proximity extension assay. We employed boosting with stability selection to establish a set of markers that was strongly associated with the PhA from a group of 233 plasma protein markers. We integrated the selected protein markers into a network and enrichment analysis to identify gene ontology (GO) terms significantly overrepresented for the selected PhA protein markers.Boosting with stability selection identified seven protein markers that were strongly and independently associated with the PhA: N-terminal prohormone brain natriuretic peptide (NT-proBNP), insulin-like growth factor-binding protein 2 (IGFBP2), adrenomedullin (ADM), myoglobin (MB), matrix metalloproteinase-9 (MMP9), protein-glutamine gamma-glutamyltransferase 2 (TGM2), and fractalkine (CX3CL1) [beta coefficient per 1 standard deviation increase in normalized protein expression values on a log 2 scale (95% confidence interval): -0.12 (-0.15, -0.08), -0.13 (-0.17, -0.09), -0.14 (-0.18, -0.10), 0.10 (0.07, 0.14), 0.07 (0.04, 0.10), 0.08 (0.05, 0.11), -0.06 (-0.10, -0.03), respectively]. According to the enrichment analysis, this protein profile was significantly overrepresented in the following top five GO terms: positive regulation of cell population proliferation (p-value: 1.32E-04), extracellular space (p-value: 1.34E-04), anatomical structure formation involved in morphogenesis (p-value: 2.92E-04), regulation of multicellular organismal development (p-value: 5.72E-04), and metal ion homeostasis (p-value: 8.86E-04).Implementing a proteomics approach, we identified six new protein markers strongly associated with the PhA and confirmed that NT-proBNP is a key PhA marker. The main biological processes that were related to this PhA's protein profile are involved in regulating the amount and growth of cells, reinforcing, from a biomedical perspective, the current technical-based consensus of the PhA to reflect body cell mass.

AIMS: Aging is accompanied by telomere shortening. Increased telomere shortening is considered a marker of premature aging. Cardiac aging results in the development of cardiac pathologies. Electrocardiogram (ECG) measures reflect cardiac excitation, conduction, and repolarization. ECG measures also prolong with aging and are associated with cardiac pathologies including atrial fibrillation. As premature prolongation of ECG measures is observed, we hypothesized that such prolongation may be associated with telomere length. METHODS AND RESULTS: We studied the large, community-based KORA F4 Study. Of 3,080 participants enrolled between 2006 and 2007 with detailed information on demographic, anthropometric, clinical, and ECG characteristics, 2,575 presented with available data on leukocyte telomere length. Telomere length was determined by real-time quantitative PCR and expressed relative to a single copy gene. We fitted multivariable adjusted linear regression models to associate the ECG measures RR-interval, PR-interval, QRS-duration, and heart rate corrected QTc with telomere length. In our cohort, the mean age was 54.9±12.9 years and 46.6% were men. Increased age was associated with shorter telomere length (p

Background Studies on the associations between lipid parameters and different hemostatic factors in men and women from the general population are scarce. It was therefore examined whether there are possible relationships between routinely measured serum lipids (total cholesterol, HDL-cholesterol, non-HDL-cholesterol, LDL-cholesterol, and triglycerides) and different hemostatic factors (activated partial thromboplastin time (aPTT), fibrinogen, factor VIII, antithrombin III (AT III), protein C, protein S, and D-dimer). Methods The analysis was based on data from the Cooperative Health Research in the Region of Augsburg (KORA)-Fit study, which included 805 participants (378 men, 427 women) with a mean age of 63.1 years. Sex-specific associations between serum lipids and coagulation factors were investigated using multivariable linear regression models. Results In men, total cholesterol was inversely related to aPTT but positively associated with protein C activity. HDL cholesterol was inversely related to aPTT and fibrinogen. LDL cholesterol, non-HDL cholesterol, and triglycerides showed a positive association with protein C and protein S activity. In women, LDL-cholesterol, total cholesterol, and non-HDL-cholesterol were positively related to AT III concentrations and protein C and S activity. Additionally, non-HDL-cholesterol was positively associated with factor VIII activity. HDL cholesterol was inversely related to fibrinogen. Triglycerides showed a positive relationship with protein C activity. Conclusions There seem to be sex differences regarding various associations between blood lipid levels and hemostatic factors. Further studies are needed to address the possible impact of these associations on cardiovascular risk and the underlying mechanisms.

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Background Inflammatory processes have been implicated in the development of chronic kidney disease (CKD). We investigated the association of a large panel of inflammatory biomarkers reflecting aspects of immunity with kidney function and CKD incidence. Methods We used data from two independent population-based studies, KORA F4 (discovery, n = 1110, mean age 70.3 years, 48.7% male) and ESTHER (replication, n = 1672, mean age 61.9 years, 43.6% male). Serum levels of biomarkers were measured using proximity extension assay technology. The association of biomarkers with estimated glomerular filtration rate (eGFR) at baseline and with incident CKD was investigated using linear and logistic regression models adjusted for cardiorenal risk factors. Independent results from prospective analyses of both studies were pooled. The significance level was corrected for multiple testing by false-discovery rate (PFDR Results In the KORA F4 discovery study, 52 of 71 inflammatory biomarkers were inversely associated with eGFR based on serum creatinine. Top biomarkers included CD40, TNFRSF9 and IL10RB. Forty-two of these 52 biomarkers were replicated in the ESTHER study. Nine of the 42 biomarkers were associated with incident CKD independent of cardiorenal risk factors in the meta-analysis of the KORA (n = 142, mean follow-up 6.5 years) and ESTHER (n = 103, mean follow-up 8 years) studies. Pathway analysis revealed the involvement of inflammatory and immunomodulatory processes reflecting cross-communication of innate and adaptive immune cells. Conclusions Novel and known biomarkers of inflammation were reproducibly associated with kidney function. Future studies should investigate their clinical utility and underlying molecular mechanisms in independent cohorts.

Gender specific all-cause mortality risk associated with a high somatic symptom burden (SSB) in a population-based cohort was investigated. The study population included 5679 women and 5861 men aged 25–74 years from the population-based MONICA/KORA Cohort. SSB was assessed following the Somatic Symptom Scale-8 and categorized as very high (≥ 95th percentile), high (60–95th percentile), moderate (30–60th percentile), and low (≤ 30th percentile). The impact of SSB on all-cause mortality risk within a mean follow-up period of 22.6 years (SD 7.1; 267,278 person years) was estimated by gender-specific Cox regression models adjusted for sociodemographic, lifestyle, somatic and psychosocial risk factors, as well as pre-existing medical conditions. Approximately 5.7% of men and 7.3% of women had very high SSB. During follow-up, 3638 (30.6%) mortality cases were observed. Men with a very-high SSB had 48% increased relative risk of mortality in comparison to men with a low SSB after adjustment for concurrent risk factors (1.48, 95% CI 1.20–1.81, p < .0001), corresponding to 2% increased risk of mortality for each 1-point increment in SSB (1.02; 95% CI 1.01–1.03; p = 0.03). In contrast, women with a very high SSB had a 22% lower risk of mortality (0.78, 95% CI 0.61–1.00, p = 0.05) and women with high SSB had an 18% lower risk of mortality (0.82; 95% CI 0.68–0.98, p = 0.03) following adjustment for concurrent risk factors. The current findings indicate that an increasing SSB is an independent risk factor for mortality in men but not in women, pointing in the direction of critical gender differences in the management of SSB, including women’s earlier health care utilization than men.

BACKGROUND: The coexistence of low muscle mass and high fat mass, two interrelated conditions strongly associated with declining health status, has been characterized by only a few protein biomarkers. High-throughput proteomics enable concurrent measurement of numerous proteins, facilitating the discovery of potentially new biomarkers. METHODS: Data derived from the prospective population-based Cooperative Health Research in the Region of Augsburg S4/FF4 cohort study (median follow-up time: 13.5years) included 1478 participants (756 men and 722 women) aged 55-74years in the cross-sectional and 608 participants (315 men and 293 women) in the longitudinal analysis. Appendicular skeletal muscle mass (ASMM) and body fat mass index (BFMI) were determined through bioelectrical impedance analysis at baseline and follow-up. At baseline, 233 plasma proteins were measured using proximity extension assay. We implemented boosting with stability selection to enable false positives-controlled variable selection to identify new protein biomarkers of low muscle mass, high fat mass, and their combination. We evaluated prediction models developed based on group least absolute shrinkage and selection operator (lasso) with 100× bootstrapping by cross-validated area under the curve (AUC) to investigate if proteins increase the prediction accuracy on top of classical risk factors. RESULTS: In the cross-sectional analysis, we identified kallikrein-6, C-C motif chemokine 28 (CCL28), and tissue factor pathway inhibitor as previously unknown biomarkers for muscle mass [association with low ASMM: odds ratio (OR) per 1-SD increase in log2 normalized protein expression values (95% confidence interval (CI)): 1.63 (1.37-1.95), 1.31 (1.14-1.51), 1.24 (1.06-1.45), respectively] and serine protease 27 for fat mass [association with high BFMI: OR (95% CI): 0.73 (0.61-0.86)]. CCL28 and metalloproteinase inhibitor 4 (TIMP4) constituted new biomarkers for the combination of low muscle and high fat mass [association with low ASMM combined with high BFMI: OR (95% CI): 1.32 (1.08-1.61), 1.28 (1.03-1.59), respectively]. Including protein biomarkers selected in ≥90% of group lasso bootstrap iterations on top of classical risk factors improved the performance of models predicting low ASMM, high BFMI, and their combination [delta AUC (95% CI): 0.16 (0.13-0.20), 0.22 (0.18-0.25), 0.12 (0.08-0.17), respectively]. In the longitudinal analysis, N-terminal prohormone brain natriuretic peptide (NT-proBNP) was the only protein selected for loss in ASMM and loss in ASMM combined with gain in BFMI over 14years [OR (95% CI): 1.40 (1.10-1.77), 1.60 (1.15-2.24), respectively]. CONCLUSIONS: Proteomic profiling revealed CCL28 and TIMP4 as new biomarkers of low muscle mass combined with high fat mass and NT-proBNP as a key biomarker of loss in muscle mass combined with gain in fat mass. Proteomics enable us to accelerate biomarker discoveries in muscle research.

Background Physical activity (PA) is a proven strategy to prevent chronic diseases and reduce falls. Furthermore, it improves or at least maintains performance of activities of daily living, and thus fosters an independent lifestyle in older adults. However, evidence on the association of PA with relevant subgroups, such as older adults with utilization of long-term care (LTC), is sparse. This knowledge would be essential for establishing effective, need-based strategies to minimize the burden on healthcare systems due to the increasing need for LTC in old age. Methods Data originate from the 2011/12 (t1) baseline assessment and 2016 (t2) follow-up of the population-based Cooperative Health Research in the Region of Augsburg (KORA-)Age study in southern Germany. In 4812 observations of individuals ≥65 years, the association between various types of PA (walking, exercise (i. e., subcategory of PA with the objective to improve or maintain one or more components of physical fitness), walking+exercise) and utilization of LTC (yes/no) was analyzed using generalized estimating equation logistic models. Corresponding models stratified by sex (females: 2499 observations; males: 2313 observations) examined sex-specific associations. Descriptive analyses assessed the proportion of individuals meeting the suggested minimum values in the German National Physical Activity Recommendations for older adults (GNPAR). Results All types of PA showed a statistically significant association with non-utilization of LTC in the entire cohort. “Walking+exercise” had the strongest association with non-utilization of LTC in the entire cohort (odds ratio (OR): 0.52, 95% confidence interval (CI): 0.39–0.70) and in males (OR: 0.41, CI: 0.26–0.65), whereas in females it was “exercise” (OR: 0.58; CI: 0.35–0.94). The proportion of individuals meeting the GNPAR was higher among those without utilization of LTC (32.7%) than among those with LTC (11.7%) and group differences were statistically significant (p ≤ 0.05). Conclusions The GNPAR are rarely met by older adults. However, doing any type of PA is associated with non-utilization of LTC in community-dwelling older adults. Therefore, older adults should be encouraged to walk or exercise regularly. Furthermore, future PA programs should consider target-groups’ particularities to reach individuals with the highest needs for support.

Background The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering. Methods Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization. Results Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71–0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = − 0.12, Wald-p = 3.63e−13), apolipoprotein B (APOB) (Wald-Ratio = − 0.09, Wald-p = 2.54e−04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e−04). Conclusions Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.

Background Little is known about the associations between cardiovascular risk factors (CRF) and disc degeneration (DD). Purpose To evaluate the potential association between CRFs and intervertebral DD in a population-based sample. Methods A total of 400 participants from the community-based KORA-study were assessed in terms of CRFs, specifically obesity, hypertension, diabetes, elevated LDL-c, low HDL-c, elevated triglycerides, smoking status, and alcohol consumption. The patients additionally underwent whole-body magnetic resonance imaging (MRI) using T2-weighted single-shot fast-spin-echo and T1 dual-echo gradient-echo Dixon pulse sequences. Thoracic and lumbar DD were assessed using the Pfirrmann score and for the presence of disc bulging/protrusion. Cross-sectional associations between CRFs and MR-based Pfirrmann score were then analyzed. Results A total of 385 individuals (58.2% men; mean age 56.3 ± 9.2 years) were included. Prevalence of DD was 76.4%. Older age (β = 0.18; 95% CI 0.12–0.25; P Conclusion A significant independent association exists between age, BMI, and intervertebral DD. In contrast, there is no significant association between cardiovascular risk factors and DD. Providing strong evidence that the pathologic process undergirding DD is mechanical, rather than microvascular, in nature.

Background Diabetes mellitus is an established risk factor for cardiovascular diseases. Even impaired levels of glucose and insulin might harm organ function prior to diabetes onset. Whether serum glucose or insulin plays a direct role in cardiac dysfunction or lung volume reduction remains unclear. The aim was to investigate the relationship between glucose and insulin with the right ventricle and lung volumes within KORA-MRI FF4 study. Methods From the KORA-MRI FF4 cohort study 337 subjects (mean age 55.7 ± 9.1 years; 43% women) underwent a whole-body 3T MRI scan. Cardiac parameters derived from a cine-steady-state free precession sequence using cvi42. MRI-based lung volumes derived semi-automatically using an in-house algorithm. Fasting serum glucose, fasting insulin levels, and HOMA index were calculated in all study subjects. Linear regression analyses were performed to assess the relationships between glucose and insulin levels with right ventricle volumes and lung volumes adjusted for age, sex, BMI, and cardiovascular risk factors. Results In univariate and multivariate-adjusted models, high serum insulin was inversely associated with end-diastolic volume (β = −12.43, P < 0.001), end-systolic volume (β = −7.12, P < 0.001), stroke volume (β = −5.32, P < 0.001), but not with ejection fraction. The association remained significant after additional adjustment for lung volumes. Similarly, serum insulin was inversely associated with lung volume (β = −0.15, P = 0.04). Sensitivity analysis confirmed results after excluding subjects with known diabetes. Conclusions Serum insulin was inversely associated with right ventricle function and lung volumes in subjects from the general population free of cardiovascular disease, suggesting that increased insulin levels may contribute to subclinical cardiopulmonary circulation impairment.

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E−04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).

To assess the stability of somatic symptoms in community-dwelling participants.The study included 2472 participants (1190 men, 1282 women; mean age 44.3 ± 10.9) from the prospective population-based MONICA-S3 cohort (1994/95) and the 10-year follow-up KORA-F3 cohort. Somatic symptoms were assessed by an adapted version of the Somatic Symptom Scale-8 (SSS-8a) with scores ranging from 0 to 24. Somatic symptom stability was assessed by weighted kappa values (κ). Generalized Estimating Equation models assessing symptom stability were adjusted for sociodemographic, lifestyle, clinical and psychosocial risk factors, as well as pre-existing medical conditions.The mean (±SD) SSS-8a was lower in men (S3: 6.88 ± 3.87, F3: 6.60 ± 3.86) than women (S3: 8.43 ± 4.0, F3: 8.31 ± 4.2) at both time points. However, somatic symptoms remained moderately stable in both genders over 10 years (κ =0.42 in men and κ = 0.48 in women), with the largest stability observed in trouble sleeping for men (κ =0.41) and pain in the joints for women (κ =0.41). Pre-existing somatic symptoms were significantly associated with increasing symptoms at follow-up [men: β = 0.82 (SE 0.12), women: β = 0.85 (SE 0.12)], followed by age and psychosocial factors, whereas higher education and recent health care utilization were inversely associated with increasing symptoms. Although hypertension and obesity were associated with increasing somatic symptoms in men, pre-existing medical conditions were not associated with increasing somatic symptoms in men nor women.The current findings indicate that somatic symptoms remain moderately stable in the general population during 10 years of follow-up, mainly driven by sociodemographic and psychosocial factors.

Since family history of diabetes is a very strong risk factor for type 2 diabetes, which is one of the most important risk factors for cardiovascular disease (CVD), it might be also useful to assess the risk for CVD. Therefore, we aimed to investigate the relationship between a familial (parents and siblings) history of diabetes and the risk of incident CVD. Data from four prospective German cohort studies were used: EPIC-Potsdam study (n = 26,054), CARLA study (n = 1,079), SHIP study (n = 3,974), and KORA study (n = 15,777). A multivariable-adjusted Cox regression was performed to estimate associations between familial histories of diabetes, myocardial infarction or stroke and the risk of CVD in each cohort; combined hazard ratios (HRMeta) were derived by conducting a meta-analysis. The history of diabetes in first-degree relatives was not related to the development of CVD (HRMeta 0.99; 95% CI 0.88–1.10). Results were similar for the single outcomes myocardial infarction (MI) (HRMeta 1.07; 95% CI 0.92–1.23) and stroke (HRMeta 1.00; 95% CI 0.86–1.16). In contrast, parental history of MI and stroke were associated with an increased CVD risk. Our study indicates that diabetes in the family might not be a relevant risk factor for the incidence of CVD. However, the study confirmed the relationship between a parental history of MI or stroke and the onset of CVD.

The correlation between physical inactivity, thoracolumbar disc degeneration, and back pain remains unclear.This study investigated the relationship between short- and long-term physical inactivity and degenerative changes of the thoracic and lumbar spine in a southern German cohort from the general population over a time period of 14 years.This study was designed as a cross-sectional case-control study, nested in a prospective cohort from the "Cooperative Health Research in the Region of Augsburg/Kooperative Gesundheitsforschung in der Region Augsburg" (KORA) study.All participants in the population-based KORA study were assessed using a physical activity questionnaire to establish a baseline in 1999-2001 (exam 1), within an initial follow up questionnaire in 2006-2008 (exam 2), and a second follow-up questionnaire between 2013 and 2014 (exam 3). A subsample of this group (400 subjects) underwent full body MR scan performed on a 3T magnetic resonance imaging scanner current with exam 3.Data regarding physical inactivity over a time period of 14 years and back pain, and quantification of thoracic and lumbar disc degeneration on magnetic resonance imaging.Quantification of thoracic and lumbar disc degeneration was performed using the Pfirrmann score. Physical activity was grouped as no physical activity, irregularly for 1 hour, regularly for 1 hour, or regularly for ≥2 hours. This was used to calculate another variable "physical inactivity," with the options of irregular activity ≤1 hour per week or regularly ≥1 hour. Physical labor, walking, and cycling activity were additionally investigated. Correlations between physical inactivity measurements and thoracic and lumbar disc degeneration were analyzed via linear regression models adjusted for age, sex, BMI, hypertension, diabetes, and back pain.In total, 385 individuals (mean age: 56 years, SD ± 9.19; 58.2% male) were included in this study. Mean summed Pfirrmann score was 2.41 (SD ± 4.19) in the thoracic and 1.78 (SD ± 1.81) in the lumbar spine. The level of current exercise in our cohort varied with 113 (29.4%) subjects exercising regularly ≥2 hours per week, 118 (30.7%) regularly 1 hour per week, 57 (14%) irregularly for about 1 hour per week, and 97 (25.2%) stated not to exercise at exam 3. Disc degeneration was more apparent in those with irregular activity1 hour compared to those with regular activity of ≥1 hour and more per week (p.01) and in those with no activity compared to those with regular activity of ≥2 (p.001) measured using exam 3. Less physical activity over a time period of 14 years correlated with an increase of disc degeneration of the thoracic and lumbar spine after adjustment for age, sex, BMI, hypertension and diabetes mellitus (p.05). There was no statistically significant association between physical labor, walking activity, or cycling activity with disc degeneration. Additionally, no significant correlations between degree of disc degeneration (p=.990), degree of physical inactivity (p=.158), and back pain were observed.Degree of physical inactivity as measured over a time period of 14 years demonstrated a strong correlation with disc degeneration of the thoracic and lumbar spine.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)—mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions—were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)—mapping respectively to SERINC2, CHST12, and an intergenic region—were associated with increased mortality risk. DNA methylation at each site predicted 5%¬¬–15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.

Background Hypertension remains a significant modifiable risk factor for cardiovascular diseases and a major determinant of morbidity and mortality. We aimed to describe sex-stratified age-standardized estimates of prevalence, awareness, treatment and control of hypertension, and their associated factors in older adults. Methods The KORA-Age1 is a population-based cross-sectional survey carried out in 2008/2009 on individuals aged 65–94 years in Augsburg region, Germany. Blood pressure measurements were available for 1052 out of 1079 persons who participated in the physical examination. Factors associated with prevalence, awareness and control of hypertension were investigated by multivariable logistic regression. Results The overall prevalence of hypertension (≥140/90 mmHg) was 73.8% [95% confidence interval (CI), 69.3–77.9], representing 74.8% (95% CI, 68.4–80.2) in men and 73.5% (95% CI, 66.8–79.3) in women. Among those with hypertension, 80.2% (95% CI, 75.3–84.4) were aware of their hypertensive condition and 74.4% (95% CI, 69.2–79.1) were on treatment for hypertension. Among those aware of their hypertension status, 92.8% (95% CI, 88.8–95.6) were on treatment and 53.7% (95% CI, 47.0–60.1) had their blood pressure controlled. Hypertension was more frequent in individuals who were older, obese, or had diabetes. Higher education attainment or presence of comorbidities was associated with higher level of hypertension awareness. Individuals taking three antihypertensive drug classes were more likely to have controlled hypertension compared with those taking one antihypertensive drug class, odds ratio (OR), 1.85 (95% CI, 1.14–2.99). Conclusion Our findings identified high prevalence of hypertension and relevant health gaps on awareness, treatment and suboptimal control of hypertension in older adults in Germany. Screening for hypertension should especially target older adults with low educational attainment and ‘healthy’ elderly with less contact to physicians.

Die korperliche Aktivitat stellt ein komplexes Verhalten dar, dessen valide und reliable Erfassung in gros angelegten populationsbasierten Studien mit besonderen Herausforderungen einhergeht. In der bundesweiten NAKO Gesundheitsstudie liegen zur Halbzeit der Basiserhebung die Daten zur korperlichen Aktivitat fur 100.000 Teilnehmende vor. Beschreibung der Erfassung der korperlichen Aktivitat und Prasentation erster deskriptiver Ergebnisse. Das multimodale Erhebungskonzept bestand aus zwei Fragebogen, dem Questionnaire on Annual Physical Activity Pattern (QUAP) und dem Global Physical Activity Questionnaire (GPAQ), einem computerbasierten Erinnerungsprotokoll der vergangenen 24 h (cpar24) und einer 7‑Tage-Akzelerometrie (Actigraph GT3X/+; Fa. ActiGraph, Pensacola, FL, USA). Fur die einzelnen Erhebungsmodule lagen auswertbare Datensatze in unterschiedlicher Zahl vor (QUAP: n = 16.372; GPAQ: n = 90.900; cpar24: n = 23.989; Akzelerometrie: n = 35.218). Die Analysen der einzelnen Module ergaben unterschiedliche Durchschnittswerte fur die moderate oder intensive korperliche Gesamtaktivitat der Teilnehmenden: Bei Frauen wurden 75–216 min/Tag gemessen, bei Mannern 73–224 min/Tag. Personen der Altersgruppe 20–39 Jahre verbrachten 66–200 min/Tag in moderater oder intensiver korperlicher Gesamtaktivitat, wahrend Personen der Altersgruppe 40–69 Jahre 78–244 min/Tag aufwendeten. Erste modulubergreifende Analysen der korperlichen Aktivitat in der NAKO zeigen den Nutzen komplementar eingesetzter Erhebungsmethoden. Die umfangreichen Daten stellen eine wertvolle Ressource fur die Charakterisierung der Zusammenhange zwischen korperlicher Aktivitat und Krankheitspravention dar, die in der Zukunft erfolgen soll.

Background: The evidence linking ambient air pollution to bladder cancer is limited and mixed. Methods: We assessed the associations of bladder cancer incidence with residential exposure to fine particles (PM2.5), nitrogen dioxide (NO2), black carbon (BC), warm season ozone (O3) and eight PM2.5 elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) in a pooled cohort (N = 302,493). Exposures were primarily assessed based on 2010 measurements and back-extrapolated to the baseline years. We applied Cox proportional hazard models adjusting for individual- and area-level potential confounders. Results: During an average of 18.2 years follow-up, 967 bladder cancer cases occurred. We observed a positive though statistically non-significant association between PM2.5 and bladder cancer incidence. Hazard Ratios (HR) were 1.09 (95% confidence interval (CI): 0.93–1.27) per 5 µg/m3 for 2010 exposure and 1.06 (95% CI: 0.99–1.14) for baseline exposure. Effect estimates for NO2, BC and O3 were close to unity. A positive association was observed with PM2.5 zinc (HR 1.08; 95% CI: 1.00–1.16 per 10 ng/m3). Conclusions: We found suggestive evidence of an association between long-term PM2.5 mass exposure and bladder cancer, strengthening the evidence from the few previous studies. The association with zinc in PM2.5 suggests the importance of industrial emissions.

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.Although our genetic code does not change throughout our lives, our genes can be turned on and off as a result of epigenetics. Epigenetics can track how the environment and even certain behaviors add or remove small chemical markers to the DNA that makes up the genome. The type and location of these markers may affect whether genes are active or silent, this is, whether the protein coded for by that gene is being produced or not. One common epigenetic marker is known as DNA methylation. DNA methylation has been linked to the levels of a range of proteins in our cells and the risk people have of developing chronic diseases. Blood samples can be used to determine the epigenetic markers a person has on their genome and to study the abundance of many proteins. Gadd, Hillary, McCartney, Zaghlool et al. studied the relationships between DNA methylation and the abundance of 953 different proteins in blood samples from individuals in the German KORA cohort and the Scottish Lothian Birth Cohort 1936. They then used machine learning to analyze the relationship between epigenetic markers found in people’s blood and the abundance of proteins, obtaining epigenetic scores or ‘EpiScores’ for each protein. They found 109 proteins for which DNA methylation patterns explained between at least 1% and up to 58% of the variation in protein levels. Integrating the ‘EpiScores’ with 14 years of medical records for more than 9000 individuals from the Generation Scotland study revealed 137 connections between EpiScores for proteins and a future diagnosis of common adverse health outcomes. These included diabetes, stroke, depression, Alzheimer’s dementia, various cancers, and inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease. Age-related chronic diseases are a growing issue worldwide and place pressure on healthcare systems. They also severely reduce quality of life for individuals over many years. This work shows how epigenetic scores based on protein levels in the blood could predict a person’s risk of several of these diseases. In the case of type 2 diabetes, the EpiScore results replicated previous research linking protein levels in the blood to future diagnosis of diabetes. Protein EpiScores could therefore allow researchers to identify people with the highest risk of disease, making it possible to intervene early and prevent these people from developing chronic conditions as they age.

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD., Physterols are cholesterol homologs derived from plants, which are found in humans through consumption of plant products. Here the authors have performed a genome-wide meta-analysis of 32 serum phytosterol traits, with evidence suggesting causality between sitosterol and coronary artery disease.

Background and ObjectivesHuman genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. However, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. We set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population.MethodsFollowing the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effects models and explored nonlinear effects in dose–response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias.ResultsWe identified 11 studies (n = 27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were female. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7–9). In meta-analyses, 1 SD increment in circulating log-transformed IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (relative risk 1.19; 95% confidence interval 1.10 to 1.28). A dose–response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias.DiscussionHigher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.

OBJECTIVES: The aim of this study was to asses adrenal gland volume by magnetic resonance imaging (MRI) and to study its role as an indirect marker of impaired glucose metabolism and hypothalamic-pituitary-adrenal (HPA) axis activation in a population-based cohort. METHODS: Asymptomatic participants were enrolled in a nested case-control study and underwent a 3-T MRI, including T1w-VIBE-Dixon sequences. For assessment of adrenal gland volume, adrenal glands were manually segmented in a blinded fashion. Impaired glucose metabolism was determined using fasting glucose and oral glucose tolerance test. Cardiometabolic risk factors were also obtained. Inter- and intrareader reliability as well as univariate and multivariate associations were derived. RESULTS: Among 375 subjects included in the analysis (58.5% male, 56.1 ± 9.1 years), 25.3% participants had prediabetes and 13.6% had type 2 diabetes (T2DM). Total adrenal gland volume was 11.2 ± 4.2 ml, and differed significantly between impaired glucose metabolism and healthy controls with largest total adrenal gland volume in T2DM (healthy controls: 10.0 ± 3.9 ml, prediabetes: 12.5 ± 3.8 ml, T2DM: 13.9 ± 4.6 ml; p

Background While risk factors for age-related diseases may increase multimorbidity (MM), early life deprivation may also accelerate the development of chronic diseases and MM. Methods This study explores the prevalence and pattern of MM in 65–71 year-old individuals born before, during, and after World War II in Southern Germany based on two large cross-sectional KORA (Cooperative Health Research in the Region of Augsburg) -Age studies in 2008/9 and 2016. MM was defined as having at least two chronic diseases, and birth periods were classified into five phases: pre-war, early war, late war, famine, and after the famine period. Logistic regression models were used to analyze the effect of the birth phases on MM with adjustment for sociodemographic and lifestyle risk factors. Furthermore, we used agglomerative hierarchical clustering to investigate the co-occurrence of diseases. Results Participants born during the late war phase had the highest prevalence of MM (62.2%) and single chronic diseases compared to participants born during the other phases. Being born in the late war phase was significantly associated with a higher odds of MM (OR = 1.83, 95% CI: 1.15–2.91) after adjustment for sociodemographic and lifestyle factors. In women, the prevalence of joint, gastrointestinal, eye diseases, and anxiety was higher, while heart disease, stroke, and diabetes were more common in men. Moreover, three main chronic disease clusters responsible for the observed associations were identified as: joint and psychosomatic, cardiometabolic and, other internal organ diseases. Conclusions Our findings imply that adverse early-life exposure may increase the risk of MM in adults aged 65–71 years. Moreover, identified disease clusters are not coincidental and require more investigation.

Background and aim Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. Methods Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8–9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603–1551). Results MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72–3.26) and 2.31 (1.67–3.20)) and cardiovascular mortality (4.28 (2.19–8.39) and 4.44 (2.25–8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. Conclusions We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.

Background Although gene-expression (GE) and protein levels are typically strongly genetically regulated, their correlation is known to be low. Here we investigate this phenomenon by focusing on the genetic background of this correlation in order to understand the similarities and differences in the genetic regulation of these omics layers. Methods and results We performed locus-wide association studies of 92 protein levels measured in whole blood for 2,014 samples of European ancestry and found that 66 are genetically regulated. Three female- and one male-specific effects were detected. We estimated the genetically regulated GE for all significant genes in 49 GTEx v8 tissues. A total of 7 proteins showed negative correlations with their respective GE across multiple tissues. Finally, we tested for causal links of GE on protein expression via Mendelian Randomization, and confirmed a negative causal effect of GE on protein level for five of these genes in a total of 63 gene-tissue pairs: BLMH, CASP3, CXCL16, IL6R, and SFTPD. For IL6R, we replicated the negative causal effect on coronary-artery disease (CAD), while its GE was positively linked to CAD. Conclusion While total GE and protein levels are only weakly correlated, we found high correlations between their genetically regulated components across multiple tissues. Of note, strong negative causal effects of tissue-specific GE on five protein levels were detected. Causal network analyses revealed that GE effects on CAD risks was in general mediated by protein levels.

INTRODUCTION: Lead exposure remains of continuing concern due to its known and suspected impacts on human health and has been designated as a priority substance for investigation in human biomonitoring studies by the EU. The aims of this study were to measure blood lead levels (BLL) in a population based cohort of middle-aged individuals without major current exposures to lead, and to compare these to historical blood lead levels obtained thirty years earlier. METHODS: The population-based KORA study from 1984 to 2001 included inhabitants of the Augsburg Region, Germany. During 2018 to 2019, a subsample of these participants (KORA-Fit) was invited for interview regarding demographic and lifestyle factors, physical examination and blood withdrawal. Blood samples were stored at -80C prior to measurement of BLL via graphite furnace atomic absorption spectroscopy (GF-AAS). Descriptive and multivariable analyses were performed. RESULTS: BLLs were measured in 3033 eligible persons aged 54 to 73, establishing a geometric mean (GM) BLL of 24.8 μg/l in 2018/19. Of these, 555 (18%) had BLL above proposed 95th percentile reference values of the German Environment Agency. Only small differences were found in BLL stratified by sociodemographic categories, however regular smokers had higher GM BLL (26.1 μg/l) compared to never smokers (23.7 μg/l), and an increasing BLL with increased wine consumption was noted. For 556 individuals, BLLs (GM: 54.0 μg/l) reduced by 35% in men and 50% in women compared to levels in 1987/88 with only 1.4% of individuals having an unchanged or increased BLL. DISCUSSION: KORA-Fit provided contemporary normative data for BLL in a Western European population without major current sources of lead exposure. Mean BLLs have fallen since the 1980s using historical BLL data which is likely linked to the ban of leaded gasoline. Nevertheless, BLLs in this population remain elevated at levels associated with morbidity and mortality.

Obesity increases the risk of cardiovascular diseases (CVD), however, whether adipose tissue relates to dyslipidemia, and consequently to cardiovascular events remains unknown. Thus, we investigated the association of adipose tissue with circulating lipoproteins and triglycerides (TG) in subjects without CVD. 384 participants from the KORA-MRI study (mean age 56.2 ± 9.2 years; 41.9% female) underwent whole-body 3T-MRI. Visceral (VAT) and subcutaneous adipose tissue (SAT) derived from T1-DIXON-sequence using a semi-automatic algorithm. Total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and TG were measured. Linear regression was applied to examine the relationships between adipose tissue, circulating lipoproteins, and TG, adjusting for risk factors. VAT was associated with total cholesterol (per SD increase) (ß = 0.39, p < 0.001). Total adipose tissue (TAT) and VAT were inversely associated with HDL (ß = −0.09, p = 0.009; ß = −0.14, p < 0.001), and positively associated with LDL (ß = 0.32, p < 0.001; ß = 0.37, p < 0.001). All adipose tissues were associated with TG (ß = 0.20, p < 0.001; ß = 0.27, p < 0.001; ß = 0.11, p = 0.004). Stratified analysis by sex and body mass index (BMI) was confirmatory in women and in individuals with BMI < 30. Our results suggest that adipose tissue plays an important role in increasing CVD risk independent of BMI, whereas gender imbalance may be explained by accurate characterization and quantification of adipose tissue.

Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess.

Iron-related disorders of the liver can result in serious health conditions, such as liver cirrhosis. Evidence on the role of modifiable lifestyle factors like nutrition in liver iron storage is lacking. Thus, we aimed to assess the association of habitual diet with liver iron content (LIC). We investigated 303 participants from the population-based KORA-MRI study who underwent whole-body magnetic resonance imaging (MRI). Dietary habits were evaluated using repeated 24 h food lists and a food frequency questionnaire. Sex-stratified multiple linear regression models were applied to quantify the association between nutrition variables of interest and LIC, adjusting for liver fat content (LFC), energy intake, and age. Mean age of participants was 56.4 ± 9.0 years and 44.2% were female. Mean LIC was 1.23 ± 0.12 mg/g dry weight, with higher values in men than in women (1.26 ± 0.13 and 1.20 ± 0.10 mg/g, p < 0.001). Alcohol intake was positively associated with LIC (men: β = 1.94; women: β = 4.98, p-values < 0.03). Significant negative associations with LIC were found for fiber (β = −5.61, p < 0.001) and potassium (β = −0.058, p = 0.034) for female participants only. Furthermore, LIC was highly correlated with liver fat content in both sexes. Our findings suggests that there are sex-specific associations of habitual dietary intake and LIC. Alcohol, fiber, and potassium may play a considerable role in liver iron metabolism.

Particulate matter air pollution and diesel engine exhaust have been classified as carcinogenic for lung cancer, yet few studies have explored associations with liver cancer. We used six European adult cohorts which were recruited between 1985 and 2005, pooled within the “Effects of low-level air pollution: A study in Europe” (ELAPSE) project, and followed for the incidence of liver cancer until 2011 to 2015. The annual average exposure to nitrogen dioxide (NO 2), particulate matter with diameter 2.5), black carbon (BC), warm-season ozone (O 3), and eight elemental components of PM 2.5 (copper, iron, zinc, sulfur, nickel, vanadium, silicon, and potassium) were estimated by European-wide hybrid land-use regression models at participants' residential addresses. We analyzed the association between air pollution and liver cancer incidence by Cox proportional hazards models adjusting for potential confounders. Of 330 064 cancer-free adults at baseline, 512 developed liver cancer during a mean follow-up of 18.1 years. We observed positive linear associations between NO 2 (hazard ratio, 95% confidence interval: 1.17, 1.02-1.35 per 10 μg/m 3), PM 2.5 (1.12, 0.92-1.36 per 5 μg/m 3), and BC (1.15, 1.00-1.33 per 0.5 10 −5/m) and liver cancer incidence. Associations with NO 2 and BC persisted in two-pollutant models with PM 2.5. Most components of PM 2.5 were associated with the risk of liver cancer, with the strongest associations for sulfur and vanadium, which were robust to adjustment for PM 2.5 or NO 2. Our study suggests that ambient air pollution may increase the risk of liver cancer, even at concentrations below current EU standards.

Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression.

Skeletal muscle mass is subjected to constant changes and is considered a good predictor for outcome in various diseases. Bioelectrical-impedance analysis (BIA) and magnetic resonance imaging (MRI) are approved methodologies for its assessment. However, muscle mass estimations by BIA may be influenced by excess intramuscular lipids and adipose tissue in obesity. The objective of this study was to evaluate the feasibility of quantitative assessment of skeletal muscle mass by MRI as compared with BIA.Subjects from a population-based cohort underwent BIA (50 kHz, 0.8 mA) and whole-body MRI including chemical-shift encoded MRI (six echo times). Abdominal muscle mass by MRI was quantified as total and fat-free cross-sectional area by a standardized manual segmentation-algorithm and normalized to subjects' body heightAmong 335 included subjects (56.3 ± 9.1 years, 56.1% male), 95 (28.4%) were obese (BMI ≥ 30 kg/mMRI-based assessment of muscle mass is feasible in population-based imaging and strongly correlated with BIA. However, the observed weaker correlation in obese subjects may explain the known limitation of BIA in obesity and promote MRI-based assessments. Thus, skeletal muscle mass parameters by MRI may serve as practical imaging biomarkers independent of subjects' body weight.

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Background The number of people using long-term care (LTC) is increasing steadily, hence, demand for adequate services is rising. The purpose of this exploratory study was to identify relevant gender-linked determinants for utilization of LTC in community-dwelling older adults. Methods We examined 4077 females (52.7%) and males ≥ 65 years old (range: 65–97 years) between 2011/12 (t1) and 2016 (t2). Data originated from the population-based Cooperative Health Research in the Region of Augsburg (KORA)-Age study in southern Germany. A descriptive analysis assessed the amount of LTC used. Cross-sectional generalized estimating equation logistic models identified determinants for utilization of (in)formal LTC. Determinants for transition to LTC between t1 and t2 were examined using a longitudinal logistic regression model. Potential determinants were chosen according to Andersen's Behavioral Model of Health Services Use. Results At t2, 820 (20.1%) were LTC users with 527 (64.3%) being female. The average amount of informal LTC was higher in males, whereas the amount of formal LTC was higher in females. In both genders, higher age, multimorbidity, and disability were associated with utilization of and transition to LTC. Living alone was significantly associated with utilization of LTC in both genders, but its effect was two times stronger in males. Thus, it is considered the essential gender-linked determinant. Conclusions Gender-linked determinants must be considered when establishing demand-oriented policies. Future health programs should specifically target older individuals, especially males, living alone to improve their capabilities in activities of daily living to allow them to remain living longer and independently within community settings.

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.

Background Compared to individuals without type 2 diabetes mellitus, the relative increase in cardiovascular mortality is much higher in women than in men in individuals with type 2 diabetes mellitus. Methods We evaluated data from 7443 individuals (3792 women, 50.9%), aged 20 to 81 years, from two independent population-based investigations, SHIP-0 and MONICA/KORA S3. We analyzed the longitudinal sex-specific associations of lipoprotein(a) with cardiovascular mortality in individuals with and without type 2 diabetes mellitus using Cox regression. Results During a median follow-up of 20.5 years (136,802 person-years), 657 participants (404 men and 253 women) died of cardiovascular causes. Among individuals without type 2 diabetes mellitus, men had a significantly higher risk for cardiovascular mortality compared to women in unadjusted model and after adjustment. On the other hand, in participants with type 2 diabetes mellitus, the risk for cardiovascular mortality was not different between men and women in the unadjusted model and after adjustment for age, body mass index, low-density lipoprotein-cholesterol, fasting status and study sample (SHIP-0, MONICA/KORA S3). Further adjustment for lipoprotein(a) concentrations had no impact on the hazard ratio (HR) for cardiovascular mortality comparing men versus women in individuals without type 2 diabetes mellitus [HR: 1.94; 95% confidence interval (CI) 1.63 to 2.32; p Conclusions Women are described to have a stronger relative increase in cardiovascular mortality than men when comparing individuals with and without type 2 diabetes mellitus. Higher lipoprotein(a) concentrations in women with type 2 diabetes mellitus than in men with type 2 diabetes mellitus might partially explain this finding.

Background Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. Methods Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). Results Kaplan–Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p 1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02–1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03–1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02–1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01–1.25, p = 0.04) and HR 1.10; 95% CI 1.01–1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. Conclusions HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups., Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.

Mathematical models are able to reflect biological processes and to capture epidemiologic data. Thus, they may help elucidate roles of risk factors in disease progression. We propose to account for smoking, hypertension, and dyslipidemia in a previously published process-oriented model that describes the development of atherosclerotic lesions resulting in myocardial infarction (MI). The model is sex-specific and incorporates individual heterogeneity. It was applied to population-based individual risk factors and MI rates (Cooperative Health Research in the Region of Augsburg (KORA) study) together with subclinical atherosclerotic lesion data (Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study). Different model variants were evaluated, testing the association of risk factors with different disease processes. Best fits were obtained for smoking affecting a late-stage disease process, suggesting a thrombogenic role. Hypertension was mainly related to complicated, vulnerable lesions. Dyslipidemia was consistent with increasing the number of initial lesions. By accounting for heterogeneity, individual hazard ratios differ from the population average. The mean individual hazard ratio for smoking was twice the population-based hazard ratio for men and even more for women. Atherosclerotic lesion progression and MI incidence data can be related in a mathematical model to illuminate how risk factors affect different phases of this pathological process.

Resettlers are a large migrant group of more than 2 million people in Germany who migrated mainly from the former Soviet Union to Germany after 1989. We sought to compare the distribution of the major risk factors for cardiovascular disease (CVD) and to investigate the overall genetic differences in a study population which consisted of resettlers and native (autochthone) Germans. This was a joint analysis of two cohort studies which were performed in the region of Augsburg, Bavaria, Germany, with 3363 native Germans and 363 resettlers. Data from questionnaires and physical examinations were used to compare the risk factors for cardiovascular diseases between the resettlers and native Germans. A population-based genome-wide association analysis was performed in order to identify the genetic differences between the two groups. The distribution of the major risk factors for CVD differed between the two groups. The resettlers lead a less active lifestyle. While female resettlers smoked less than their German counterparts, the men showed similar smoking behavior. SNPs from three genes (BTNL2, DGKB, TGFBR3) indicated a difference in the two populations. In other studies, these genes have been shown to be associated with CVD, rheumatoid arthritis and osteoporosis, respectively.

Publisher's version (útgefin grein)., Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles., This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338. Study-specific acknowledgements can be found in the Supplementary Notes 2 and 4. The data on coronary artery disease have been contributed by the Myocardial Infarction Genetics and CARDIoGRAM investigators, and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.

Background: Associations between several persistent organic pollutants (POPs) and type 2 diabetes have been found in humans, but the relationship has rarely been investigated in the general population. The current nested case-control study examined internal exposure to polychlorinated biphenyls (PCB) and pesticides and the incidence of type 2 diabetes among participants of two population-based German cohort studies. Methods: We retrospectively selected 132 incident cases of type 2 diabetes and 264 age- and sex-matched controls from the CARdiovascular Living and Aging in Halle (CARLA) study (2002–2006, East Germany) and the Cooperative Health Research in the Region of Augsburg (KORA) study (1999–2001, South Germany) based on diabetes status at follow-up examinations in 2007–2010 and 2006–08, respectively (60% male, mean age 63 and 54 years). We assessed the association between baseline POP concentrations and incident diabetes by conditional logistic regression adjusted for cohort, BMI, cholesterol, alcohol, smoking, physical activity, and parental diabetes. Additionally, we examined effect modification by sex, obesity, parental diabetes and cohort. Results: In both cohorts, diabetes cases showed a higher BMI, a higher frequency of parental diabetes, and higher levels of POPs. We observed an increased chance for incident diabetes for PCB-138 and PCB-153 with an odds ratio (OR) of 1.50 (95%CI: 1.07–2.11) and 1.53 (1.15–2.04) per interquartile range increase in the respective POP. In addition, explorative results suggested higher OR for women and non-obese participants. Conclusions: Our results add to the evidence on diabetogenic effects of POPs in the general population, and warrant both policies to prevent human exposure to POPs and additional research on the adverse effects of more complex chemical mixtures. Keywords: Type 2 diabetes, Incidence, Environmental contaminates, Case-control study, Epidemiology

Objective:The origin of malnutrition in older age is multifactorial and risk factors may vary according to health and living situation. The present study aimed to identify setting-specific risk profiles of malnutrition in older adults and to investigate the association of the number of individual risk factors with malnutrition.Design:Data of four cross-sectional studies were harmonized and uniformly analysed. Malnutrition was defined as BMI < 20 kg/m2 and/or weight loss of >3 kg in the previous 3–6 months. Associations between factors of six domains (demographics, health, mental function, physical function, dietary intake-related problems, dietary behaviour), the number of individual risk factors and malnutrition were analysed using logistic regression.Setting:Community (CD), geriatric day hospital (GDH), home care (HC), nursing home (NH).Participants:CD older adults (n 1073), GDH patients (n 180), HC receivers (n 335) and NH residents (n 197), all ≥65 years.Results:Malnutrition prevalence was lower in CD (11 %) than in the other settings (16–19 %). In the CD sample, poor appetite, difficulties with eating, respiratory and gastrointestinal diseases were associated with malnutrition; in GDH patients, poor appetite and respiratory diseases; in HC receivers, younger age, poor appetite and nausea; and in NH residents, older age and mobility limitations. In all settings the likelihood of malnutrition increased with the number of potential individual risk factors.Conclusions:The study indicates a varying relevance of certain risk factors of malnutrition in different settings. However, the relationship of the number of individual risk factors with malnutrition in all settings implies comprehensive approaches to identify persons at risk of malnutrition early.

Accurate prediction of relevant outcomes is important for targeting therapies and to support health economic evaluations of healthcare interventions in patients with diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) risk equations are some of the most frequently used risk equations. This study aims to analyze the calibration and discrimination of the updated UKPDS risk equations as implemented in the UKPDS Outcomes Model 2 (UKPDS-OM2) for predicting cardiovascular (CV) events and death in patients with type 2 diabetes mellitus (T2DM) from population-based German samples. Analyses are based on data of 456 individuals diagnosed with T2DM who participated in two population-based studies in southern Germany (KORA (Cooperative Health Research in the Region of Augsburg)-A: 1997/1998, n = 178; KORA-S4: 1999–2001, n = 278). We compared the participants’ 10-year observed incidence of mortality, CV mortality, myocardial infarction (MI), and stroke with the predicted event rate of the UKPDS-OM2. The model’s calibration was evaluated by Greenwood–Nam–D’Agostino tests and discrimination was evaluated by C-statistics. Of the 456 participants with T2DM (mean age 65 years, mean diabetes duration 8 years, 56% male), over the 10-year follow-up time 129 died (61 due to CV events), 64 experienced an MI, and 46 a stroke. The UKPDS-OM2 significantly over-predicted mortality and CV mortality by 25% and 28%, respectively (Greenwood–Nam–D’Agostino tests: p

Background: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes.Methods: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation–validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days.Results: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set.Conclusions: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.)

Animal sterols, plant sterols and bile acids in stool samples have been suggested as biomarkers of dietary intake. It is still unknown whether they also reflect long-term habitual dietary intake and can be used in aetiological research. In a subgroup of the Cooperative Health Research in the Augsburg Region (KORA FF4) study, habitual dietary intake was estimated based on repeated 24-h food list and a FFQ. Stool samples were collected according to a standard operating procedure and those meeting the quality criteria were extracted and analysed by means of a metabolomics technique. The present study is based on data from 513 men and 495 women with a mean age of 60 and 58 years, respectively, for which faecal animal and plant sterols and bile acids concentrations and dietary intake data were available. In adjusted regression models, the associations between food intake and log-normalised metabolite concentrations were analysed. Bonferroni correction was used to account for multiple testing. In this population-based sample, associations between habitual dietary intake and faecal concentrations of animal sterols were identified, while the impact of usual diet on bile acids was limited. A habitual diet high in ‘fruits’ and ‘nuts and seeds’ is associated with lower animal faecal sterols concentrations, whereas a diet high in ‘meat and meat products’ is positively related to faecal concentrations of animal sterols. A positive association between glycocholate and fruit consumption was found. Further studies are necessary for evaluation of faecal animal sterols as biomarkers of diet. The findings need to be confirmed in other populations with diverse dietary habits.

Purpose Inter-individual metabolic differences may be a reason for previously inconsistent results in diet–diabetes associations. We aimed to investigate associations between dietary intake and diabetes for metabolically homogeneous subgroups (‘metabotypes’) in a large cross-sectional study. Methods We used data of 1517 adults aged 38–87 years from the German population-based KORA FF4 study (2013/2014). Dietary intake was estimated based on the combination of a food frequency questionnaire and multiple 24-h food lists. Glucose tolerance status was classified based on an oral glucose tolerance test in participants without a previous diabetes diagnosis using American Diabetes Association criteria. Logistic regression was applied to examine the associations between dietary intake and diabetes for two distinct metabotypes, which were identified based on 16 biochemical and anthropometric parameters. Results A low intake of fruits and a high intake of total meat, processed meat and sugar-sweetened beverages (SSB) were significantly associated with diabetes in the total study population. Stratified by metabotype, associations with diabetes remained significant for intake of total meat (OR 1.67, 95% CI 1.04–2.67) and processed meat (OR 2.23, 95% CI 1.24–4.04) in the metabotypes with rather favorable metabolic characteristics, and for intake of fruits (OR 0.83, 95% CI 0.68–0.99) and SSB (OR:1.21, 95% CI 1.09–1.35) in the more unfavorable metabotype. However, only the association between SSB intake and diabetes differed significantly by metabotype (p value for interaction = 0.01). Conclusions Our findings suggest an influence of metabolic characteristics on diet–diabetes associations, which may help to explain inconsistent previous results. The causality of the observed associations needs to be confirmed in prospective and intervention studies. Electronic supplementary material The online version of this article (10.1007/s00394-019-01988-5) contains supplementary material, which is available to authorized users.

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of ‘transcriptomic’ MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10− 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis. Electronic supplementary material The online version of this article (10.1007/s00439-019-01994-x) contains supplementary material, which is available to authorized users.