Stool and blood metabolomics in the metabolic syndrome: a cross-sectional study.

INTRODUCTION/OBJECTIVES: Changes in the stool metabolome have been poorly studied in the metabolic syndrome (MetS). Moreover, few studies have explored the relationship of stool metabolites with circulating metabolites. Here, we investigated the associations between stool and blood metabolites, the MetS and systemic inflammation. METHODS: We analyzed data from 1,370 participants of the KORA FF4 study (Germany). Metabolites were measured by Metabolon, Inc. (untargeted) in stool, and using the AbsoluteIDQ® p180 kit (targeted) in blood. Multiple linear regression models, adjusted for dietary pattern, age, sex, physical activity, smoking status and alcohol intake, were used to estimate the associations of metabolites with the MetS, its components and high-sensitivity C-reactive protein (hsCRP) levels. Partial correlation and Multi-Omics Factor Analysis (MOFA) were used to investigate the relationship between stool and blood metabolites. RESULTS: The MetS was significantly associated with 170 stool and 82 blood metabolites. The MetS components with the highest number of associations were triglyceride levels (stool) and HDL levels (blood). Additionally, 107 and 27 MetS-associated metabolites (in stool and blood, respectively) showed significant associations with hsCRP levels. We found low partial correlation coefficients between stool and blood metabolites. MOFA did not detect shared variation across the two datasets. CONCLUSIONS: The MetS, particularly dyslipidemia, is associated with multiple stool and blood metabolites that are also associated with systemic inflammation. Further studies are necessary to validate our findings and to characterize metabolic alterations in the MetS. Although our analyses point to weak correlations between stool and blood metabolites, additional studies using integrative approaches are warranted.

Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study.

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 < 0.05) from the fully-adjusted model. RESULTS: In the KORA F4 sample, after Bonferroni correction, we found CHD to be associated with five proteins using the age-sex adjusted model: galectin-4 (LGALS4), renin (REN), cathepsin H (CTSH), and coagulation factors X and Xa (F10). The fully-adjusted model yielded only the positive association of galectin-4 (OR = 1.58, 95% CI = 1.30-1.93), which was successfully replicated in the KORA F3 sample (OR = 1.40, 95% CI = 1.09-1.88). For CIMT, we found four proteins to be associated using the age-sex adjusted model namely: cytoplasmic protein NCK1 (NCK1), insulin-like growth factor-binding protein 2 (IGFBP2), growth hormone receptor (GHR), and GDNF family receptor alpha-1 (GFRA1). After assessing the fully-adjusted model, only NCK1 remained significant (ß = 0.017, p-value = 1.39e-06). Upstream regulators of galectin-4 and NCK1 identified from pathway analysis were predicted to be involved in inflammation pathways. CONCLUSIONS: Our proteome-wide association study identified galectin-4 to be associated with CHD and NCK1 to be associated with CIMT. Inflammatory pathways underlying the identified associations highlight the importance of inflammation in the development and progression of CHD.

Autoimmune diseases and female-specific cancer risk: A systematic review and meta-analysis.

OBJECTIVES: Among the over 80 different autoimmune diseases, psoriasis (PsO), rheumatoid arthritis (RA), and ankylosing spondylitis (AS) are common representatives. Previous studies indicated a potential link with cancer risk, but suffered often from low statistical power. Thus, we aimed to synthesize the evidence and quantify the association to different female-specific cancer sites. METHODS: The systematic review was performed according to PRISMA guidelines. A search string was developed for the databases PubMed, Web of Science, Cochrane Library and Embase. Results were screened independently by two investigators and the risk of bias was assessed using the ROBINS-E tool. Meta-analyses were performed using inverse variance weighted random-effects models. Statistical between-study heterogeneity was quantified by calculating Cochran's Q, τ2, and Higgins' I2 statistics. Sources of heterogeneity were analyzed and adjusted for within an intensive bias assessment in the form of meta-regression, outlier, influential, and subgroup analyses. A range of methods were used to test and adjust for publication bias. RESULTS: Of 10,096 records that were originally identified by the search strategy, 45 were included in the meta-analyses. RA was inversely associated with both breast and uterine cancer occurrence, while PsO was associated with a higher breast cancer risk. Outlier-adjusted estimates confirmed these findings. Bias assessment revealed differences in geographic regions, particularly in RA patients, with higher estimates among Asian studies. An additional analysis revealed no association between psoriatic arthritis and breast cancer. CONCLUSIONS: RA seems to reduce the risk of breast and uterine cancers, while PsO appears to increase breast cancer risk. Further large studies are required to investigate potential therapy-effects and detailed biological mechanisms.

Association of Aldosterone with Mortality in the General Population.

INTRODUCTION: Aldosterone excess is linked to cardiovascular events and mortality as well as to low-grade inflammation in the context of metabolic diseases. Whether mildly elevated aldosterone levels in the general population promote cardiovascular risk is still under debate. We analyzed the association of plasma aldosterone concentrations with incident cardiovascular events, cardiovascular and all-cause mortality as well as with biomarkers of subclinical inflammation in the population-based KORA F4 study. METHODS: Plasma aldosterone concentrations were measured with an in-house immunoflurometric assay. The analyses included 2935 participants (n=1076 for selected biomarkers of subclinical inflammation) with a median follow-up of 8.7 (8.2; 9.1) years. The associations were estimated using Cox proportional hazard and linear regression models adjusted for renin, sex, age, body mass index, arterial hypertension, diabetes, estimated glomerular filtration rate, low- and high-density lipoprotein cholesterol, physical activity, smoking, use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, diuretics and calcium channel blockers. RESULTS: Aldosterone was significantly associated with all-cause mortality (hazard ratio per standard deviation increase: 1.20; 95% confidence interval 1.04-1.37), but not with cardiovascular mortality, incident cardiovascular events, or with biomarkers of subclinical inflammation. CONCLUSIONS: Aldosterone was associated with all-cause mortality in the population-based KORA F4 study, but the previously described associations of excess aldosterone with cardiovascular complications and biomarkers of subclinical inflammation could not be shown.

[Regional Differences in Thyroid Function Parameters: A Comparison of European Cohort Studies]. / Regionale Unterschiede von Schilddrüsenfunktionsparametern: ein Vergleich europäischer Kohortenstudien.

AIM OF THE STUDY: The aim of the project was to investigate regional differences in thyroid stimulating hormone (TSH), and free thyroxine (fT4) concentrations and iodine status in comparable German and European cohort studies. METHODS: Sex- and age-stratified TSH, fT4, and urine iodine concentrations of thyroid-healthy participants (age group 45-75 years) of the HNR (Heinz Nixdorf Recall) Study in the Ruhr region of Germany, the southern German KORA (Cooperative Health Research in the Augsburg Region) and northeastern German SHIP (Study of Health in Pomerania) studies, as well as the Norwegian HUNT (Nord-Trøndelag Health) study (age group 40-79 years), the English EPIC (European Prospective Investigation of Cancer)-Norfolk study, and the Dutch Rotterdam study were compared. The TSH reference range for the HNR study population was calculated and compared to the KORA and SHIP studies. RESULTS: Regional differences showed a stronger influence on TSH and fT4 concentrations than sex and age of the subjects in the 45- to 75-year age group. The estimated difference in medians, as measured by the HNR study, was lowest in the SHIP study, -0.47 (95% CI: -0.53; -0.41) for men and -0.41 (-0.53; -0.41) for women. The Rotterdam study had the highest difference in medians for both men and women (men: 0.56 with 0.44; 0.68 and women: 0.62 with 0.46; 0.78). The lowest median TSH concentrations, across all age categories considered, were seen in the German cohorts. CONCLUSIONS: Comparison of thyroid function parameters and iodine in elderly subjects between six comparable cohort studies from Germany and Europe showed a significant influence of region, which exceeded the sex and age dependence of the parameters.

Long-Term Predictors of Hospitalized Reinfarction after an Incident Acute Myocardial Infarction.

The aim of this study was to compare characteristics of incident acute myocardial infarction (AMI) and first and second time reinfarctions in terms of sociodemographic characteristics, comorbidities, symptoms, treatment, clinical characteristics, medication and outcome. A further aim was to identify predictors for an increased risk of hospitalized reinfarction. Between 2000 and 2017, a total of 13,276 AMI cases were recorded by a population-based registry in the area of Augsburg, Germany, and were included in this study (11,871 incident events, 1217 cases of first-time reinfarction and 202 cases of second-time reinfarction). Median follow-up time was 5.3 years. For differences in baseline characteristics, Chi-square tests and analysis of variance (ANOVA) were calculated. To determine factors that are associated with an increased risk of hospitalized reinfarction COX regression models were fitted. Myocardial reinfarctions differ from incident events in some major characteristics such as the frequency of comorbidities, laboratory values, ECG presentation and therapy, but not regarding 28-day mortality. Moreover, typical comorbidities and risk factors (diabetes, hypertension, hyperlipidemia, smoking, impaired renal function) are associated with an increased risk of hospitalized reinfarction. Conversely, STEMI ECG, being married, German nationality and bypass surgery are predictors for a lower risk of hospitalized reinfarction. Incident AMI and reinfarction are distinctly different in many characteristics, which physicians should have in mind when treating patients with prior AMI. Typical comorbidities are risk factors for hospitalized reinfarction. This underlines the importance of comprehensive treatment of these comorbidities including education of patients and encouragement towards lifestyle adjustments.

Association of C-Terminal Pro-Endothelin-1 with Mortality in the Population-Based KORA F4 Study.

Introduction: Endothelin-1 and its prohormone C-terminal pro-endothelin-1 (CT-proET-1) have been linked to metabolic alterations, inflammatory responses and cardiovascular events in selected study populations. We analyzed the association of CT-proET-1 with cardiovascular events and mortality, carotid intima-media-thickness as surrogate for early atherosclerotic lesions, biomarkers of subclinical inflammation and adipokines in a population-based study. Methods: The cross-sectional and prospective analyses used data from the KORA F4 study with a median follow-up time of 9.1 (8.8-9.4) years. Data on CT-proET-1 and mortality were available for 1554 participants, data on the other outcomes in subgroups (n = 596-1554). The associations were estimated using multivariable linear regression and Cox proportional hazard models adjusted for sex, age, body mass index, estimated glomerular filtration rate, arterial hypertension, diabetes, low-density and high-density lipoprotein cholesterol, current and former smoking and physical activity. The Bonferroni method was used to correct for multiple testing. Results: In the fully adjusted model, CT-proET-1 was associated with cardiovascular (hazard ratio (HR) per standard deviation increase: 1.66; 95% confidence interval (CI): 1.10-2.51; p = 0.017) and all-cause mortality (HR: 2.03; 95% CI 1.55-2.67; p < 0.001), but not with cardiovascular events, and was inversely associated with the intima-media thickness (ß: -0.09 ± 0.03; p = 0.001). CT-proET-1 was positively associated with five out of ten biomarkers of subclinical inflammation and with two out of five adipokines after correction for multiple testing. After inclusion of biomarkers of subclinical inflammation in the Cox proportional hazard model, the association of CT-proET-1 with all-cause mortality persisted (p < 0.001). Conclusion: These results emphasize the complexity of endothelin-1 actions and/or indicator functions of CT-proET-1. CT-proET-1 is a risk marker for all-cause mortality, which is likely independent of vascular endothelin-1 actions, cardiovascular disease and inflammation.

Rheumatoid arthritis and inflammatory bowel disease: A bidirectional two-sample Mendelian randomization study.

OBJECTIVES: An association between arthritis and inflammatory bowel disease (IBD) was found in observational studies. However, neither the direction nor the cause-effect chain is clear. METHODS: A two-sample Mendelian randomization study was carried out to investigate whether rheumatoid arthritis is causally related to IBD and vice versa. Independent genetic instruments from the largest available genome-wide association study (GWAS) for rheumatoid arthritis (29,880 cases and 73,758 controls) were used to investigate the association with IBD in a sample including European participants (12,882 cases; 21,770 controls). Primary analyses were conducted using the radial inverse-variance weighted (IVW) approach. A number of sensitivity analyses were carried out to assess the robustness of the results. RESULTS: We found a positive effect of genetically predicted rheumatoid arthritis on IBD as a whole (OR 1.214; 95% CI 1.134; 1.299; P = 3 × 10-8). In subtype analyses rheumatoid arthritis was suggestively associated with Crohn's disease (CD) (OR 1.108; 95% CI 1.024; 1.199; P = 0.011) and ulcerative colitis (UC) (OR 1.082; 95% CI 1.002; 1.168; P = 0.044). Regarding the other direction, IBD as a whole as well as both subtypes were not related to rheumatoid arthritis. CONCLUSIONS: The present study provides evidence for a link between rheumatoid arthritis and IBD as a whole as well as both subtypes UC and CD. In the other direction no associations could be found. These findings support the clinical need for screening IBD in patients with rheumatoid arthritis.

Population-based cohort imaging: skeletal muscle mass by magnetic resonance imaging in correlation to bioelectrical-impedance analysis.

BACKGROUND: 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. METHODS: 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 height2 (abdominal muscle mass indices: AMMIMRI ). RESULTS: Among 335 included subjects (56.3 ± 9.1 years, 56.1% male), 95 (28.4%) were obese (BMI ≥ 30 kg/m2 ). MRI-based and BIA-based measures of muscle mass were strongly correlated, particularly in non-obese subjects [r < 0.74 in non-obese (P < 0.001) vs. r < 0.56 in obese (P < 0.001)]. Median AMMITotal(MRI) was significantly higher in obese as compared with non-obese subjects (3246.7 ± 606.1 mm2 /m2 vs. 2839.0 ± 535.8 mm2 /m2 , P < 0.001, respectively), whereas the ratio AMMIFat-free /AMMITotal (by MRI) was significantly higher in non-obese individuals (59.3 ± 10.1% vs. 53.5 ± 10.6%, P < 0.001, respectively). No significant difference was found regarding AMMIFat-free(MRI) (P = 0.424). In analyses adjusted for age and sex, impaired glucose tolerance and measures of obesity were significantly and positively associated with AMMITotal(MRI) and significantly and inversely with the ratio AMMIFat-free(MRI) /AMMITotal(MRI) (P < 0.001). CONCLUSIONS: MRI-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.

Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study.

BACKGROUND: Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. METHODS: To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). RESULTS: Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn's disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. CONCLUSIONS: This study supports a causal effect between AD and IBD-but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.