Aims
To assess the association of circulating concentrations of angiopoietin‐2 (Ang‐2) and its soluble receptor Tie‐2 (sTie‐2) with all‐cause, cardiovascular, and cancer mortality in a ...population‐based sample.
Methods and results
Angiopoietin‐2 and sTie‐2 were measured in 3220 participants (1665 women; mean age 54.4 years) in the Study of Health in Pomerania (SHIP). Multivariable adjusted hazard ratios (HRs) for mortality were estimated using Cox proportional hazard models. During a median follow‐up of 6.2 years, 217 participants died. Ang‐2 levels were positively associated with all‐cause mortality HR 1.29; 95% confidence interval (CI) 1.19–1.39 per 1 SD increment; P < 0.001 and cardiovascular mortality (HR 1.32; 95% CI 1.18–1.49; P < 0.001), but not with cancer mortality (HR 1.08; 95% CI 0.89–1.32; P = 0.416). Levels of sTie‐2 were not significantly related to all‐cause mortality (HR 1.12; 95% CI 0.98–1.27; P = 0.102). Adding Ang‐2 to a prediction model for all‐cause mortality with standard risk factors slightly improved discrimination (Δ Harrell's C, 0.008; P < 0.001) but not risk reclassification (continuous net reclassification improvement, −0.015; P = 0.571).
Conclusion
In our community‐based sample, higher serum Ang‐2 concentrations were associated with greater risk for all‐cause and cardiovascular mortality, suggesting that subtle increases in Ang‐2 levels might reflect processes such as vascular remodelling that are associated with higher mortality risk. Adding Ang‐2 to a mortality prediction model only modestly improved discrimination.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
ContextIt is assumed that hepatic steatosis plays a role in the development and progression of the metabolic syndrome and its cardiovascular sequelae. Low serum IGF1 levels might mediate these ...associations.ObjectivesThe aims of this study were i) to investigate the associations of hepatic steatosis with serum IGF1 and IGF binding protein-3 (IGFBP-3) levels using ultrasound and serum alanine aminotransaminase (ALT) data to define hepatic steatosis, and ii) to analyze the specific role of alcohol consumption in this context.DesignWe analyzed data from the population-based Study of Health in Pomerania.MethodsWe used data from 3863 subjects (1971 women) aged 20–79 years who had no history of viral hepatitis, liver cirrhosis, or malignant diseases. Liver hyperechogenicity was diagnosed using ultrasound. Serum IGF1 and IGFBP-3 levels were determined by automated two-site chemiluminescence immunoassays.ResultsHyperechogenic liver pattern was associated with low serum IGF1 levels and low serum IGF1/IGFBP-3 ratios. The lowest serum IGF1 and IGF1/IGFBP-3 values and highest IGFBP-3 levels were present in subjects who had a hyperechogenic liver pattern and increased serum ALT levels. All of these associations were independent of alcohol consumption.ConclusionsOur data show that hepatic steatosis is associated with low serum IGF1 levels. This association is independent of alcohol consumption.
Background
Fibroblast growth factor 23 (FGF23) is emerging as a novel biomarker of bone metabolism, chronic kidney disease, and cardiovascular disease (CVD). However, its clinical correlates and ...potential predictive role in a community‐based setting are incompletely understood.
Methods and Results
We evaluated participants of the Framingham Heart Study (seventh examination cycle of the Offspring cohort plus second examination cycle of the multiethnic Omni cohort) to identify clinical correlates of plasma FGF23 (N=3236) and examine its cross‐sectional association with vascular function (N=2209), and longitudinal association with 10‐year incidence of CVD (N=2823), and all‐cause mortality (N=3223).
Circulating FGF23 concentrations were positively related to African‐American and Asian ethnicity, waist circumference, current smoking, serum glucose, history of CVD, and antihypertensive medication use; and negatively related to male sex, hormone replacement therapy, and estimated glomerular filtration rate. Multivariable‐adjusted cross‐sectional analyses showed no consistent association of FGF23 with vascular function measures. During a median follow‐up time of 10.8 years, 347 incident CVD events and 412 deaths occurred. Multivariable‐adjusted Cox regression models revealed a positive association of FGF23 with all‐cause mortality (hazard ratio HR per SD increase, 1.31; 95% CI, 1.20–1.42), but not with incident CVD (HR per SD increase, 1.05; 95% CI, 0.94–1.17).
Conclusions
In our large, community‐based sample, FGF23 was associated with mortality risk, but not with vascular function or incident CVD.
Microarray profiling of gene expression is widely applied in molecular biology and functional genomics. Experimental and technical variations make meta-analysis of different studies challenging. In a ...total of 3358 samples, all from German population-based cohorts, we investigated the effect of data preprocessing and the variability due to sample processing in whole blood cell and blood monocyte gene expression data, measured on the Illumina HumanHT-12 v3 BeadChip array.Gene expression signal intensities were similar after applying the log(2) or the variance-stabilizing transformation. In all cohorts, the first principal component (PC) explained more than 95% of the total variation. Technical factors substantially influenced signal intensity values, especially the Illumina chip assignment (33-48% of the variance), the RNA amplification batch (12-24%), the RNA isolation batch (16%), and the sample storage time, in particular the time between blood donation and RNA isolation for the whole blood cell samples (2-3%), and the time between RNA isolation and amplification for the monocyte samples (2%). White blood cell composition parameters were the strongest biological factors influencing the expression signal intensities in the whole blood cell samples (3%), followed by sex (1-2%) in both sample types. Known single nucleotide polymorphisms (SNPs) were located in 38% of the analyzed probe sequences and 4% of them included common SNPs (minor allele frequency >5%). Out of the tested SNPs, 1.4% significantly modified the probe-specific expression signals (Bonferroni corrected p-value<0.05), but in almost half of these events the signal intensities were even increased despite the occurrence of the mismatch. Thus, the vast majority of SNPs within probes had no significant effect on hybridization efficiency.In summary, adjustment for a few selected technical factors greatly improved reliability of gene expression analyses. Such adjustments are particularly required for meta-analyses.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bone production, maintenance, and modeling are a well-balanced process involving mineralization by osteoblasts and resorption by osteoclasts. Sex steroid hormones, including their conjugated forms, ...contribute majorly to maintaining this balance. Recently, variants in the
gene have been associated with osteoporosis in Korean females. We had recently shown that
, encoding organic anion transporter 7 (OAT7), is an uptake transporter of estrone sulfate and identified several genetic variants in Europeans leading to functional consequences
. We therefore hypothesized that
genetic variants may contribute to the pathophysiology of osteoporosis in Europeans. To test this hypothesis, we examined the associations of
variants with bone quality, fractures, and bone turnover markers. We genotyped
variants in 5,701 (2,930 female) subjects (age range, 20-93 years) extracted from the population-based Study of Health in Pomerania (SHIP and SHIP-TREND) covered by the Illumina Infinium HumanExome BeadChip version v1.0 (Exome Chip). Descriptive data (e.g., history of fractures), ultrasonography of the calcaneus, as well as serum concentrations of carboxy-terminal telopeptide of type I collagen, amino-terminal propeptide of type I procollagen, and vitamin D were determined. Comprehensive statistical analyses revealed no association between low-frequency and rare
variants and bone quality, fractures, and bone turnover markers. Our results indicate that single genetic
variants do not have a major impact on osteoporosis risk prediction in Europeans, yet findings need to be replicated in larger-scale studies.
The role of androgens in metabolism with respect to sex-specific disease associations is poorly understood. Therefore, we aimed to provide molecular signatures in plasma and urine of androgen action ...in a sex-specific manner using state-of-the-art metabolomics techniques. Our study population consisted of 430 men and 343 women, aged 20-80 years, who were recruited for the cross-sectional population-based Study of Health in Pomerania (SHIP-TREND), Germany. We used linear regression models to identify associations between testosterone, androstenedione and dehydroepiandrosterone-sulfate (DHEAS) as well as sex hormone-binding globulin and plasma or urine metabolites measured by mass spectrometry. The analyses revealed major sex-specific differences in androgen-associated metabolites, particularly for levels of urate, lipids and metabolic surrogates of lifestyle factors, like cotinine or piperine. In women, in particular in the postmenopausal state, androgens showed a greater impact on the metabolome than in men (especially DHEAS and lipids were highly related in women). We observed a novel association of androstenedione on the metabolism of biogenic amines and only a small sex-overlap of associations within steroid metabolism. The present study yields new insights in the interaction between androgens and metabolism, especially about their implication in female metabolism.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To investigate potential associations of serum prolactin concentration (PRL) with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM), previously observed in small and selected study ...samples, in a large population-based cohort.
Data from 3,993 individuals (2,027 women) aged 20-79 years from the population-based Study of Health of Pomerania (SHIP) were used to analyse cross-sectional and longitudinal associations of PRL with MetS and T2DM risk in age- and multivariable-adjusted Poisson regression models. PRL were log-transformed and modelled as continuous (per standard deviation (SD) increase) and categorical predictor (sex-specific quartiles) variable, separately for men and woman.
Cross-sectional analyses showed an inverse association between low PRL concentrations and prevalent T2DM risk in men and women after multivariable-adjustment (men: Q1 vs. Q4: relative risk (RR), 1.55; 95% confidence interval (CI), 1.13 - 2.14; women: Q1 vs. Q4: RR, 1.70; 95% CI, 1.10 - 2.62). Likewise, higher PRL concentrations were associated with significantly lower T2DM risk (RR per SD increase in log-PRL: 0.83; 95% CI, 0.72 - 0.95 in men, and 0.84; 95% CI, 0.71 - 0.98 in women, respectively). An inverse association between PRL and MetS risk was not retained after multivariable adjustment. Longitudinal analyses yielded no association of PRL with incident MetS or T2DM.
The present study is the first large population-based study reporting a cross-sectional inverse association between PRL and prevalent T2DM in both genders. But the absent longitudinal associations do not support a causal role of PRL as a risk factor of incident MetS or T2DM.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
L-Arginine and its dimethylated derivatives asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been associated with cardiovascular (CV) and all-cause mortality in ...populations at risk. The present study aimed to investigate the prognostic value of L-arginine and its derivatives in the general population.
We evaluated 3,952 individuals (1,936 men and 2,016 women) aged 20-81 (median (IQR) 51 (37; 64) years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous per standard deviation (SD) increase and categorized (age- and sex-specific tertiles) serum L-arginine, ADMA, and SDMA concentrations with all-cause and cause-specific mortality were analysed. During a median (IQR) follow-up period of 10.1 (9.3; 10.8) years (38,476 person-years), 426 deaths (10.8%) were observed, including 139 CV deaths (3.5%), and 150 cancer deaths (3.8%). After multivariable adjustment, we revealed a positive association of SDMA with all-cause hazard ratio (HR) per SD increase: 1.16, 95% confidence interval (CI): 1.07-1.25 and CV mortality HR: 1.19, 95% CI: 1.05-1.35. In contrast, we did not observe any association of SDMA with cancer mortality. Neither L-arginine nor ADMA were associated with all-cause or CV mortality.
SDMA, but not ADMA, is an independent predictor of all-cause and CV mortality in a large population-based cohort of European ancestry.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with ...increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p = 2.61 × 10(-19)), ARPC1A (rs740160; p = 1.56 × 10(-16)), TRIM4 (rs17277546; p = 4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p = 4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent research suggested a metabolic implication of osteocalcin (OCN) in e.g. insulin sensitivity or steroid production. We used an untargeted metabolomics approach by analyzing plasma and urine ...samples of 931 participants using mass spectrometry to reveal further metabolic actions of OCN. Several detected relations between OCN and metabolites were strongly linked to renal function, however, a number of associations remained significant after adjustment for renal function. Intermediates of proline catabolism were associated with OCN reflecting the implication in bone metabolism. The association to kynurenine points towards a pro-inflammatory state with increasing OCN. Inverse relations with intermediates of branch-chained amino acid metabolism suggest a link to energy metabolism. Finally, urinary surrogate markers of smoking highlight its adverse effect on OCN metabolism. In conclusion, the present study provides a read-out of metabolic actions of OCN. However, most of the associations were weak arguing for a limited role of OCN in whole-body metabolism.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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