Left ventricular hypertrophy as a risk factor for accelerated brain aging: Results from the Study of Health in Pomerania.

Previous studies provided evidence for the importance of cardiac structure abnormalities, in particular greater left ventricular (LV) mass, for brain aging, but longitudinal studies are lacking to date. We included 926 individuals (median age 48 years; 53% women) from the TREND cohort of the Study of Health in Pomerania (SHIP) without reduced ejection fraction or a history of myocardial infarction. LV mass index (LVMI) was determined by echocardiography at baseline. Brain morphometric measurements were derived from magnetic resonance images at baseline and 7-year follow-up. Direct effects of baseline LVMI on brain morphometry at follow-up were estimated using linear regression models with adjustment for baseline brain morphometry. At baseline, median LVMI was 40 g/m2.7 and 241 individuals (26%) met the criterion of LV hypertrophy. After correction for multiple testing, baseline LVMI was directly associated with reduced global cortical thickness and increased cortical brain age at follow-up independent from hypertension and blood pressure. Exposure-outcome relations were nonlinear and significantly stronger in the upper half of the exposure distribution. Specifically, an increase in baseline LVMI from the 50% quantile to the 95% quantile was associated additional 2.7 years (95% confidence interval = [1.5 years, 3.8 years]) of cortical brain age at follow-up. Additional regional analyses yielded bilateral effects on multiple frontal cortical regions. Our findings highlight the role of cardiac structure in brain aging. LVMI constitutes an easily measurable marker that might help to identify persons at risk for cognitive impairment and dementia.

Deep learning-based NT-proBNP prediction from the ECG for risk assessment in the community.

OBJECTIVES: The biomarker N-terminal pro B-type natriuretic peptide (NT-proBNP) has predictive value for identifying individuals at risk for cardiovascular disease (CVD). However, it is not widely used for screening in the general population, potentially due to financial and operational reasons. This study aims to develop a deep-learning model as an efficient means to reliably identify individuals at risk for CVD by predicting serum levels of NT-proBNP from the ECG. METHODS: A deep convolutional neural network was developed using the population-based cohort study Hamburg City Health Study (HCHS, n=8,253, 50.9 % women). External validation was performed in two independent population-based cohorts (SHIP-START, n=3,002, 52.1 % women, and SHIP-TREND, n=3,819, 51.2 % women). Assessment of model performance was conducted using Pearson correlation (R) and area under the receiver operating characteristics curve (AUROC). RESULTS: NT-proBNP was predictable from the ECG (R, 0.566 [HCHS], 0.642 [SHIP-START-0], 0.655 [SHIP-TREND-0]). Across cohorts, predicted NT-proBNP (pNT-proBNP) showed good discriminatory ability for prevalent and incident heart failure (HF) (baseline: AUROC 0.795 [HCHS], 0.816 [SHIP-START-0], 0.783 [SHIP-TREND-0]; first follow-up: 0.669 [SHIP-START-1, 5 years], 0.689 [SHIP-TREND-1, 7.3 years]), comparable to the discriminatory value of measured NT-proBNP. pNT-proBNP also demonstrated comparable results for other incident CVD, including atrial fibrillation, stroke, myocardial infarction, and cardiovascular death. CONCLUSIONS: Deep learning ECG algorithms can predict NT-proBNP concentrations with high diagnostic and predictive value for HF and other major CVD and may be used in the community to identify individuals at risk. Long-standing experience with NT-proBNP can increase acceptance of such deep learning models in clinical practice.

Serum lipoprotein subfractions are associated with the periodontal status: Results from the population-based cohort SHIP-TREND.

AIM: To investigate the medium-term associations of serum protein subfractions derived from proton nuclear magnetic resonance (1 H-NMR) spectroscopy with periodontitis and tooth loss. MATERIALS AND METHODS: A total of 3031 participants of the cohort Study of Health in Pomerania (SHIP-TREND) were included. In addition to conventional serum testing, serum lipoprotein contents and subfractions were analysed by 1 H-NMR spectroscopy. Confounder-adjusted associations of lipoprotein variables with periodontitis and the number of missing teeth variables were analysed using mixed-effects models with random intercepts for time across individuals, accounting for multiple testing. RESULTS: While only spurious associations between lipoprotein levels from conventional blood tests were found-that is, triglycerides were associated with mean clinical attachment level (CAL) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with the number of missing teeth - several associations emerged from serum lipoprotein subfractions derived from 1 H-NMR analysis. Specifically, elevated LDL triglycerides were associated with higher levels of mean probing depth (PD), mean CALs, and increased odds of having <20 teeth. HDL-4 cholesterol levels were inversely associated with mean PD. Systemic inflammation (C-reactive protein) might mediate the effects of LDL and HDL triglyceride contents on periodontitis severity. CONCLUSIONS: Several associations between serum lipoprotein subfractions and periodontitis were observed. As the underlying biochemical mechanisms remain unclear, further research is needed.

Body composition markers are associated with changes in inflammatory markers but not vice versa: A bi-directional longitudinal analysis in a population-based sample.

BACKGROUND AND AIM: Growing body of evidence consistently link obesity and inflammation, Although the direction of the association is still unclear. We aimed to investigate longitudinal associations of body anthropometric, composition and fat distribution parameters with inflammatory markers and vice versa. METHOD AND RESULTS: We used data from 2464 individuals of the SHIP-TREND cohort with a median follow-up of 7 years. Linear regression models adjusted for confounders were used to analyze associations of standardized body composition markers derived from classic anthropometry, bioelectrical impedance analysis (BIA) and magnetic resonance imaging (MRI) at baseline with changes in inflammatory markers (C-reactive protein (CRP), white blood cell (WBC), fibrinogen) and vice versa. Higher level of anthropometric markers at baseline were associated with an increase in the change of inflammatory markers. A 13.5 cm higher waist circumference (WC), 16.0 kg body weight and 7.76 % relative fat mass (FM) at baseline was associated with a change in CRP of 0.52 mg/L (95 % confidence interval [CI]: 0.29 to 0.74), 0.51 mg/L (95 % CI: 0.29; 0.74) and 0.58 mg/L (95 % CI: 0.34; 0.82) respectively. Absolute FM showed the strongest association with changes in serum fibrinogen levels (ß for 8.69 kg higher FM: 0.07 g/L; 95 % CI: 0.05; 0.09). Baseline inflammatory markers were only associated with changes in hip circumference. CONCLUSION: Our study indicates the importance of anthropometric, body composition and fat distribution markers as a risk factor for the development of inflammation. To prevent inflammatory-related complications, important is to take measures against the development of obesity.

Association of plasma chemerin with all-cause and disease-specific mortality - results from a population-based study.

BACKGROUND AND OBJECTIVES: Various cross-sectional studies have observed an association between high circulating concentrations of the adipokine chemerin and an unfavorable metabolic profile. However, the prognostic value of chemerin for the risk of associated diseases and mortality was examined only in a few studies mostly using small and highly selected patient populations. We aimed to analyze the association between plasma chemerin concentrations and all-cause as well as cause-specific mortality in the general population. STUDY DESIGN AND METHODS: From the Study of Health in Pomerania (SHIP), participants of two independent cohorts (SHIP-START-1 [n = 3037], SHIP-TREND-0 [n = 4193]) were followed up for 15 and 9 years (median), respectively. The association between plasma chemerin and all-cause mortality was analyzed using multivariable Cox proportional hazard regression models. Additionally, cause-specific hazards for cardiovascular disease (CVD) and cancer mortality were modeled considering competing events. RESULTS: A total number of 507 and 208 deaths occurred during follow-up in SHIP-START-1 and SHIP-TREND-0, respectively. Multivariable regression analyses revealed a significant association between high plasma chemerin concentrations and greater overall mortality that was independent of major confounders. Each 30 ng/mL increase in chemerin was associated with a 17% higher risk of all-cause mortality (95%-confidence interval: 1.10-1.26). Cause-specific analyses further showed that the chemerin concentration was significantly associated with cancer mortality but not with CVD mortality. CONCLUSION: The present study detected a positive association between plasma chemerin concentrations and all-cause mortality in a large population-based study sample. Cause-specific analyses have shown that chemerin is likely to play a decisive role in cancer-related deaths. However, a direct association with cardiovascular mortality could not be established.

An arrhythmogenic metabolite in atrial fibrillation.

BACKGROUND: Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. METHODS AND RESULTS: Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. CONCLUSION: Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF.

Identification of candidate metabolite biomarkers for metabolic syndrome and its five components in population-based human cohorts.

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

Carotid intima-media thickness and atherosclerotic plaques are associated with renal function decline: a 14-year longitudinal population-based study.

BACKGROUND: Chronic kidney disease (CKD) leads to increased morbidity and mortality. The underlying causes of CKD are often similar to those of atherosclerosis. We investigated whether carotid atherosclerotic parameters are associated with renal function decline. METHODS: Within the population-based Study of Health in Pomerania (SHIP), Germany, 2904 subjects were observed over 14 years. The carotid intima-media thickness (cIMT) as well as carotid plaques were measured by standardized B-mode ultrasound protocol. CKD is defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and albuminuria as urinary albumin-creatinine ratio (ACR) ≥30 mg/g. eGFR was calculated by the full age spectrum (FAS) equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Mixed models were applied to associate carotid parameters with change in renal function longitudinally and adjusted for confounding. RESULTS: The age range of the study sample was 25-86 years with a median of 54 years at baseline. In longitudinal analyses, subjects with high cIMT and the presence of plaques at baseline showed a greater decrease in eGFR (cIMT: FAS-eGFR: P < .001, CKD-EPI-eGFR: P < .001; plaques: FAS-eGFR: P < .001, CKD-EPI-eGFR: n.s.) as well as an increased risk of developing CKD during the follow-up (cIMT: FAS-eGFR: P = .001, CKD-EPI-eGFR: P = .04; plaques: FAS-eGFR: P = .008, CKD-EPI-eGFR: P = .001). There was no association between atherosclerotic parameters and the risk of developing albuminuria. CONCLUSIONS: cIMT and carotid plaques are associated with renal function decline as well as CKD in a population-based sample. Furthermore, the FAS equation adapts best to this study population.

Body composition markers from classic anthropometry, bioelectrical impedance analysis, and magnetic resonance imaging are associated with inflammatory markers in the general population.

BACKGROUND AND AIM: The associations of body composition markers derived from different modalities with inflammatory markers are unclear. The aim of this study was to determine associations of the body composition markers from different modalities with inflammatory markers in a population-based study. METHODS AND RESULTS: We analyzed data from 4048 participants (2081 women, 51.4%) aged 20-84 years. Linear regression models adjusted for confounding were used to analyze the association of classic anthropometry markers, absolute and relative fat mass, absolute fat-free mass (FFM), and body cell mass (BCM) assessed by bioelectrical impedance analysis, subcutaneous, visceral, and liver fat from magnetic resonance imaging (MRI), with markers of inflammation. We found positive associations of classic anthropometry markers, total body fat, subcutaneous, visceral, and liver fat, with all inflammatory markers. Waist circumference (WC) showed the strongest association with high-sensitivity C-reactive protein (hsCRP) (ß: 1.39; 95% confidence interval [CI]: 1.22 to 1.56) and white blood cell (WBC) (0.39; 0.29 to 0.48), whereas visceral fat showed the strongest association with ferritin (41.9; 34.7 to 49.0). Relative body fat was strongly associated with hsCRP (1.39; 1.20 to 1.58), fibrinogen (0.29; 0.27 to 0.32), and WBC (0.35; 0.25 to 0.46). Conversely, we found inverse associations of body height, FFM, and BCM with hsCRP, fibrinogen, and WBC. CONCLUSIONS: Our study indicates the importance of WC as an easily measured marker for early inflammation. MRI-assessed markers of central obesity seem to be most strongly related to ferritin.

Low-grade inflammation is associated with a heterogeneous lipoprotein subclass profile in an apparently healthy population sample.

BACKGROUND AND AIMS: Prevention measures for cardiovascular diseases (CVD) have shifted their focus from lipoproteins to the immune system. However, low-grade inflammation and dyslipidemia are tightly entangled. The objective of this study was to assess the relations between a broad panel of inflammatory biomarkers and lipoprotein subclass parameters. METHODS: We utilized data from the population-based Study of Health in Pomerania (SHIP-TREND, n = 403). Plasma concentrations of 37 inflammatory markers were measured by a bead-based assay. Furthermore, we employed nuclear magnetic resonance spectroscopy to measure total cholesterol, total triglycerides, total phospholipids as well as the fractional concentrations of cholesterol, triglycerides, phospholipids, ApoA1, ApoA2 and ApoB in all major lipoprotein subclasses. Associations between inflammatory biomarkers and lipoprotein subclasses were analyzed by adjusted linear regression models. RESULTS: APRIL, BAFF, TWEAK, sCD30, Pentraxin-3, sTNFR1, sTNFR2, Osteocalcin, Chitinase 3-like 1, IFN-alpha2, IFN-gamma, IL-11, IL-12p40, IL-29, IL-32, IL-35, TSLP, MMP1 and MMP2 were related with lipoprotein subclass components, forming two distinct clusters. APRIL had inverse relations to HDL-C (total and subclasses) and HDL Apo-A1 and Apo-A2 content. MMP-2 was inversely related to VLDL-C (total and subclasses), IDL-C as well as LDL5/6-C and VLDL-TG, IDL-TG, total triglycerides as well as LDL5/5-TG and HDL4-TG. Additionally, we identified a cluster of cytokines linked to the Th1-immune response, which were associated with an atherogenic lipoprotein profile. CONCLUSION: Our findings expand the existing knowledge of inflammation-lipoprotein interactions, many of which are suggested to be involved in the pathogeneses of chronic non-communicable diseases. The results of our study support the use of immunomodulatory substances for the treatment and possibly prevention of CVD.

Association of spermidine plasma levels with brain aging in a population-based study.

INTRODUCTION: Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD). METHODS: Data from 659 participants (age range: 21-81 years) of the population-based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]). RESULTS: Higher spermidine levels were significantly associated with lower hippocampal volume (ß = -0.076; 95% confidence interval [CI]: -0.13 to -0.02; q = 0.026), higher AD score (ß = 0.118; 95% CI: 0.05 to 0.19; q = 0.006), lower global CT (ß = -0.104; 95% CI: -0.17 to -0.04; q = 0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis. DISCUSSION: Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.

Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study.

RATIONALE & OBJECTIVE: Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 4,951 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 or overt proteinuria (urinary albumin-creatinine ratio > 300 mg/g or equivalent). EXPOSURE: Serum levels of H-FABP and hs-TNT were measured at study entry. OUTCOME: Noncardiovascular (non-CV) death, CV death, combined major adverse CV events (MACE), and hospitalization for congestive heart failure (CHF). ANALYTICAL APPROACH: Hazard ratios (HRs) for associations of H-FABP and hs-TNT with outcomes were estimated using Cox regression analyses adjusted for established risk factors. RESULTS: During a maximum follow-up of 6.5 years, 579 non-CV deaths, 190 CV deaths, 522 MACE, and 381 CHF hospitalizations were observed. In Cox regression analyses adjusted for established risk factors, H-FABP was associated with all 4 outcomes, albeit with lower HRs than those found for hs-TNT. After further adjustment for hs-TNT levels, H-FABP was found to be associated with non-CV death (HR, 1.57 [95% CI, 1.14-2.18]) and MACE (HR, 1.40 [95% CI, 1.02-1.92]) but with neither CV death (HR, 1.64 [95% CI, 0.90-2.99]) nor CHF hospitalizations (HR, 1.02 [95% CI, 0.70-1.49]). LIMITATIONS: Single-point measurements of H-FABP and hs-TNT. Uncertain generalizability to non-European populations. CONCLUSIONS: In this large cohort of patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT. Whether measurement of H-FABP improves cardiovascular disease risk prediction in these patients warrants further studies.

A metabolome-wide association study in the general population reveals decreased levels of serum laurylcarnitine in people with depression.

Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a metabolome-wide association analysis to investigate the link between the serum metabolome and depressed mood (DM) in 1411 participants of the KORA (Cooperative Health Research in the Augsburg Region) F4 study (discovery cohort). Serum metabolomics data comprised 353 unique metabolites measured by Metabolon. We identified 72 (5.1%) KORA participants with DM. Linear regression tests were conducted modeling each metabolite value by DM status, adjusted for age, sex, body-mass index, antihypertensive, cardiovascular, antidiabetic, and thyroid gland hormone drugs, corticoids and antidepressants. Sensitivity analyses were performed in subcohorts stratified for sex, suicidal ideation, and use of antidepressants. We replicated our results in an independent sample of 968 participants of the SHIP-Trend (Study of Health in Pomerania) study including 52 (5.4%) individuals with DM (replication cohort). We found significantly lower laurylcarnitine levels in KORA F4 participants with DM after multiple testing correction according to Benjamini/Hochberg. This finding was replicated in the independent SHIP-Trend study. Laurylcarnitine remained significantly associated (p value < 0.05) with depression in samples stratified for sex, suicidal ideation, and antidepressant medication. Decreased blood laurylcarnitine levels in depressed individuals may point to impaired fatty acid oxidation and/or mitochondrial function in depressive disorders, possibly representing a novel therapeutic target.

The site of waist measurement impacts the estimation of visceral fat: results from three-dimensional photonic body scanning.

Currently, various protocols regarding the site of waist circumference (WC) measurement are in place. This study aimed to analyse the effect of the site of WC measurement on visceral adipose tissue (VAT) estimation. WC was obtained at 7 anatomical sites in 211 German volunteers (103 males) aged 23-81 years using three-dimensional photonic body scanning (PBS). At one site, WC was additionally measured by tape. The quantity of VAT was assessed by MRI. Models to estimate VAT based on WC were developed; the precision of the estimation is represented by R2. The influence of the applied method of WC assessment (tape v. PBS) on the estimations is reported. Results show that the amount of estimated VAT and the precision of VAT estimation were dependent on the site of measurement. VAT was estimated most precisely by WC taken at the level of the lowest rib (WCrib: R2 = 0·75 females; 0·79 males), the minimum circumference (WCmin: R2 = 0·75 females; 0·77 males) and at the narrowest part of the torso (WCnar: R2 = 0·76 females; 0·77 males), and least precisely by WC assessed at the top of iliac crest (WCiliac: R2 = 0·61 females; 0·60 males). VAT estimates based on WC obtained by PBS were smaller and estimations were slightly less precise compared to estimates based on tape measures. Our results indicate that the method and the site of waist measurement should be considered when estimating VAT based on WC. The implementation of a standardised protocol using either WCrib, WCmin or WCnar could improve the precision of VAT estimation.

Association of Cardiopulmonary Exercise Capacity and Adipokines in the General Population.

Adipokines and cardiorespiratory fitness (CRF) are associated with the (patho)physiology of cardiometabolic diseases. Whether CRF and adipokines are related is unclear. We investigated associations of CRF with leptin, adiponectin, chemerin, resistin and vaspin. Data from the population-based Study of Health in Pomerania was used (n=1,479; median age 49 years; 51% women). Cardiopulmonary exercise testing was used to measure CRF. Circulating adipokine concentrations were measured by enzyme-linked immunosorbent assay. The association between CRF and adipokines was assessed using multivariable sex-specific quantile regression models. Higher maximum oxygen uptake was significantly associated with lower leptin (men:-0.11 ng/ml; 95%-confidence interval [CI]:-0.18 to-0.03 ng/ml; p<0.005; women:-0.17 ng/ml; 95%-CI:-0.33 to-0.02 ng/ml; p<0.05) and chemerin (men:-0.26 ng/ml; 95%-CI:-0.52 to-0.01 ng/ml; p<0.05; women:-0.41 ng/ml; 95%-CI:-0.82 to-0.01 ng/ml; p<0.05) as well as higher adiponectin concentrations (men: 0.06 µg/ml; 95%-CI: 0.02 to 0.11 µg/ml; p<0.05; women: 0.03 µg/ml; 95%-CI:-0.05 to 0.10 µg/ml; p=0.48). We found that CRF was inversely associated with leptin and chemerin in both sexes and positively associated with adiponectin only in men.

Effect of periodontal treatment on preclinical Alzheimer's disease-Results of a trial emulation approach.

INTRODUCTION: We investigated the relationship between periodontal treatment and pre-clinical Alzheimer's disease (AD). METHODS: In this quasi-experimental design, 177 periodontally treated patients from the "Greifswald Approach to Individualized Medicine" cohort, which used the same protocols as the population-based Study of Health in Pomerania TREND (SHIP-TREND), and 409 untreated subjects from SHIP-TREND were analyzed. Subjects were younger than 60 years at the magnetic resonance imaging examination, with a median observation period of 7.3 years. Imaging markers for brain atrophy in late-onset AD and brain aging were used as the outcomes. RESULTS: Robust to sensitivity analyses, periodontal treatment had a favorable effect on AD-related brain atrophy (-0.41; 95% confidence interval: -0.70 to -0.12; P = .0051), which corresponds to a shift from the 50th to the 37th percentile of the outcome distribution. For brain aging, the treatment effect was uncertain. CONCLUSION: Periodontitis is related to pre-clinical AD in our population.

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Physical activity and cardiorespiratory fitness-A ten-year follow-up.

Physical activity (PA) may influence cardiorespiratory fitness (CRF). Yet, PA takes place in different domains (i.e., sports-related physical activity [SPA], leisure time related physical activity [LTPA], and work-related physical activity [WPA]) and not all domain-specific PA may help to maintain high CRF levels throughout life. We assessed the relationship between changes in domain-specific PA and the age-related decline in CRF. We analyzed data of 353 men (median age 50 years; inter-quartile range [IQR] 40 to 60) and 335 women (median age 50 years; IQR 41 to 59) with data for domain-specific PA as well as CRF testing measured ten years apart. CRF was assessed with cardiorespiratory exercise testing. Domain-specific PA was measured using the Baecke questionnaire. During the 10-year follow-up, CRF decreased in men from 29.3 (IQR 25.0 to 34.7) mL/min/kg to 24.3 (IQR 20.8 to 27.3) mL/min/kg. In women, CRF declined from 26.0 (IQR 21.0 to 30.9) to 21.4 (IQR 18.3 to 25.6) mL/min/kg. A one point higher SPA at baseline was related to a 1.14 (95% confidence interval [CI] -1.50 to -0.53) mL/min/kg greater decrease in VO2peak . A one point greater SPA and LTPA over time was associated with a 1.68 (95% CI 1.06 to 2.29) mL/min/kg and 1.24 (95% CI 0.57 to 1.90) mL/min/kg lower decrease in VO2peak , respectively. Neither baseline values nor changes of WPA were associated with CRF. Sports and leisure time related PA may attenuate the age-related decline in CRF.

Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation.

Epigenetic regulation of cellular function provides a mechanism for rapid organismal adaptation to changes in health, lifestyle and environment. Associations of cytosine-guanine di-nucleotide (CpG) methylation with clinical endpoints that overlap with metabolic phenotypes suggest a regulatory role for these CpG sites in the body's response to disease or environmental stress. We previously identified 20 CpG sites in an epigenome-wide association study (EWAS) with metabolomics that were also associated in recent EWASs with diabetes-, obesity-, and smoking-related endpoints. To elucidate the molecular pathways that connect these potentially regulatory CpG sites to the associated disease or lifestyle factors, we conducted a multi-omics association study including 2474 mass-spectrometry-based metabolites in plasma, urine and saliva, 225 NMR-based lipid and metabolite measures in blood, 1124 blood-circulating proteins using aptamer technology, 113 plasma protein N-glycans and 60 IgG-glyans, using 359 samples from the multi-ethnic Qatar Metabolomics Study on Diabetes (QMDiab). We report 138 multi-omics associations at these CpG sites, including diabetes biomarkers at the diabetes-associated TXNIP locus, and smoking-specific metabolites and proteins at multiple smoking-associated loci, including AHRR. Mendelian randomization suggests a causal effect of metabolite levels on methylation of obesity-associated CpG sites, i.e. of glycerophospholipid PC(O-36: 5), glycine and a very low-density lipoprotein (VLDL-A) on the methylation of the obesity-associated CpG loci DHCR24, MYO5C and CPT1A, respectively. Taken together, our study suggests that multi-omics-associated CpG methylation can provide functional read-outs for the underlying regulatory response mechanisms to disease or environmental insults.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of âˆ¼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.