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Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P

BACKGROUND/OBJECTIVES: Studies of the effect of vitamin B12 and folate on the risk of asthma and hay fever have shown inconsistent results that may be biased by reverse causation and confounding. We used a Mendelian randomization approach to examine a potential causal effect of vitamin B12 and folate on hay fever, asthma, and selected biomarkers of allergy by using 11 vitamin B12-associated single-nucleotide polymorphisms (SNPs) and 2 folate-associated SNPs as unconfounded markers.SUBJECTS/METHODS: We included 162,736 participants from 9 population-based studies including the UK Biobank. Results were combined in instrumental variable and meta-analyses and effects expressed as odds ratios (ORs) or estimates with 95% confidence interval (CI).RESULTS: Using genetic proxies for B12 and folate, instrumental variable analyses did not show evidence for associations between serum B12 and hay fever: OR = 1.02 (95% CI: 0.98, 1.05), asthma: OR = 0.99 (95% CI: 0.95, 1.04), allergic sensitization: OR = 1.02 (95% CI: 0.74, 1.40), or change in serum IgE: 10.0% (95% CI: -9.6%, 29.6%) per 100 pg/ml B12. Similarly, there was no evidence for association between serum folate and hay fever: OR = 0.74 (95% CI: 0.45, 1.21), asthma: OR = 0.80 (95% CI: 0.43, 1.49), or allergic sensitization: OR = 1.92 (95% CI: 0.11, 33.45), but there was a statistically significant association with change in serum IgE: 2.0% (95% CI: 0.43%, 3.58%) per 0.1 ng/ml serum folate.CONCLUSIONS: Our results did not support the hypothesis that levels of vitamin B12 and folate are causally related to hay fever, asthma, or biomarkers of allergy, but we found evidence of a positive association between serum folate and serum total IgE.

Aim Metabolomics provides information on pathogenetic mechanisms and targets for interventions, and may improve risk stratification. During the last decade, metabolomics studies were used to gain deeper insight into the pathogenesis of diabetes mellitus. However, longitudinal metabolomics studies of possible subclinical states of disturbed glucose metabolism are limited. Therefore, the aim of this study was to analyze the associations between baseline urinary metabolites and 5-year changes in continuous markers of glucose homoeostasis, including fasting glucose, HbA 1c and homoeostasis model assessment of insulin resistance (HOMA-IR) index values. Methods Urine metabolites in 3986 participants at both baseline and 5-year follow-up of the population-based Inter99 study were analyzed by 1 H-NMR spectroscopy. Linear regression and analyses of covariance models were used to detect associations between urine metabolites and 5-year changes in markers of glucose homoeostasis. Results Higher baseline levels of urinary alanine, betaine, N,N-dimethylglycine (DMG), creatinine and trimethylamine were associated with an increase in HbA 1c from baseline to follow-up. In contrast, formic acid and trigonelline levels were associated with a decrease in HbA 1c over time. Analyses of 5-year changes in fasting glucose and HOMA-IR index showed similar findings, with high baseline levels of lactic acid, beta-d-glucose, creatinine, alanine and 1-methylnicotinamide associated with increases in both parameters. Conclusion Several urine metabolites were found to be associated with detrimental longitudinal changes in biomarkers of glucose homoeostasis. The identified metabolites point to mechanisms involving betaine and coffee metabolism as well as the possible influence of the gut microbiome.

Different normalization methods are available for urinary data. However, it is unclear which method performs best in minimizing error variance on a certain data-set as no generally applicable empirical criteria have been established so far. The main aim of this study was to develop an applicable and formally correct algorithm to decide on the normalization method without using phenotypic information. We proved mathematically for two classical measurement error models that the optimal normalization method generates the highest correlation between the normalized urinary metabolite concentrations and its blood concentrations or, respectively, its raw urinary concentrations. We then applied the two criteria to the urinary 1H-NMR measured metabolomic data from the Study of Health in Pomerania (SHIP-0; n = 4068) under different normalization approaches and compared the results with in silico experiments to explore the effects of inflated error variance in the dilution estimation. In SHIP-0, we demonstrated consistently that probabilistic quotient normalization based on aligned spectra outperforms all other tested normalization methods. Creatinine normalization performed worst, while for unaligned data integral normalization seemed to most reasonable. The simulated and the actual data were in line with the theoretical modeling, underlining the general validity of the proposed criteria. The problem of choosing the best normalization procedure for a certain data-set can be solved empirically. Thus, we recommend applying different normalization procedures to the data and comparing their performances via the statistical methodology explicated in this work. On the basis of classical measurement error models, the proposed algorithm will find the optimal normalization method.

The identification of phenotype-driven network modules in complex, multifluid metabolomics data poses a considerable challenge for statistical analysis and result interpretation. This is the case for phenotypes with only few associations ('sparse' effects), but, in particular, for phenotypes with a large number of metabolite associations ('dense' effects). Herein, we postulate that examining the data at different layers of resolution, from metabolites to pathways, will facilitate the interpretation of modules for both the sparse and the dense cases. We propose an approach for the phenotype-driven identification of modules on multifluid networks based on untargeted metabolomics data of plasma, urine, and saliva samples from the German Study of Health in Pomerania (SHIP-TREND) study. We generated a hierarchical, multifluid map of metabolism covering both metabolite and pathway associations using Gaussian graphical models. First, this map facilitates a fundamental understanding of metabolism within and across fluids for our study, and can serve as a valuable and downloadable resource. Second, based on this map, we then present an algorithm to identify regulated modules that associate with factors such as gender and insulin-like growth factor I (IGF-I) as examples of traits with dense and sparse associations, respectively. We found IGF-I to associate at the rather fine-grained metabolite level, while gender shows well-interpretable associations at pathway level. Our results confirm that a holistic and interpretable view of metabolic changes associated with a phenotype can only be obtained if different layers of metabolic resolution from multiple body fluids are considered., Metabolomics: phenotype-driven modules in a multifluid metabolic map Metabolism consists of complex interactions across various organs and body fluids, which poses a substantial challenge for the analysis of metabolic data. To address this problem, Jan Krumsiek from Helmholtz Zentrum München and colleagues used metabolomics measurements of plasma, urine, and saliva from 1000 people to statistically reconstruct a map of interactions in human metabolism. Based on this map, a novel approach that identifies highly correlated biochemical modules that are associated with a given phenotype, was tested for gender and insulin-like growth factor I (IGF-I). The identified modules provided insights into the interaction between metabolome and phenotype that reach beyond what can be found by commonly used statistical approaches for metabolomics. The approach is generic and can be readily applied to new datasets by other colleagues from the field.

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.

BACKGROUND: Excessive salt intake causes increased blood pressure which is considered the leading risk for premature death. One major challenge when evaluating associations between daily salt intake and markers of non-communicable diseases is that a high daily salt intake correlates with obesity, which is also a well described risk factor for poor cardiometabolic outcome. The aim of this study was to evaluate the relationship of estimated daily salt intake with blood pressure and blood lipids and to investigate the effect of taking different measures of obesity into account.METHODS: We included 3294 men and women aged 18-69 years from a general population based study in Copenhagen, Denmark. Estimated 24-hour sodium excretion was calculated by measurements of creatinine and sodium concentration in spot urine in combination with information of sex, age, height and weight. The relations of estimated 24-hour sodium excretion with blood pressure and blood lipids were evaluated by linear regression models.RESULTS: The daily mean estimated intake of salt was 10.80 g and 7.52 g among men and women, respectively. Daily salt intake was significantly associated with blood pressure (β-estimates 1.18 mm Hg/g salt (systolic) and 0.74 mm Hg/g salt (diastolic), p CONCLUSIONS: Associations of estimated daily salt intake with blood pressure and blood lipids were highly affected by adjustment for obesity.

The variation in laboratory measurements represents a challenge in clinical practice and epidemiological research. The use of different analytical platforms might have led to different results, which were often discussed in the interpretation of conflicting results. We aim to study the impact of two different IGF-I and IGF binding protein 3 assays on published epidemiological studies.We compared epidemiological results based on the previous gold standard Nichols Advantage, which is no longer available, with these based on the IDS-iSYS assay. The latter follows the recently proposed Keswick criteria. We reinvestigated published association studies between IGF-I or IGF binding protein 3 and anthropometry, subclinical cardiovascular diseases including intima-media thickness or left ventricular mass index, and hard end points like mortality and single-nucleotide polymorphisms of our genome-wide association study in the Study of Health in Pomerania.We demonstrated that there are significant differences in the associations of IGF-I measured by the Nichols or IDS-iSYS assay and subclinical outcomes including intima-media thickness and left ventricular mass index. However, concerning hard outcomes like mortality or single-nucleotide polymorphisms, our analyses revealed similar results with comparable regression estimates.With our study we queried not only the accuracy of measurement but also the effect of different methods on study results. The establishment of laboratory standards like the Keswick criteria should be enforced to allow reliable comparisons of different methods and thus clinical and epidemiological studies. Single-center studies have to be interpreted carefully. Moreover, to assure the reliability of studies, their results should be replicated in a meta-analysis, and a generated hypothesis by epidemiology should be proven by intervention studies.

BackgroundPrevious intervention studies in patients with GH disorders suggested an impact of IGF1 and IGF-binding protein 3 (IGFBP3) on lipid metabolism, whereas population-based studies revealed conflicting results. Therefore, we aimed to assess the cross-sectional and longitudinal associations between IGF1 or IGFBP3 serum levels and lipids (total, LDL, or HDL cholesterol and triglycerides) in a large-scale study.MethodsData of 2935 subjects (1356 women) from the population-based Study of Health in Pomerania (SHIP) were used. ANOVA, quantile regression, and logistic regression models adjusted for age, waist circumference, physical activity, and alcohol consumption were performed.ResultsIn cross-sectional analyses, we detected that IGF1 and IGFBP3 levels were positively related to total and LDL cholesterol and inversely related to HDL cholesterol in both sexes. Furthermore, IGFBP3 levels showed a positive relationship to triglycerides. In total, IGFBP3 levels were more strongly associated to lipids than IGF1. In longitudinal analysis, we found no influence of baseline IGF1 or IGFBP3 serum concentration on incidentally elevated or reduced lipid levels. However, the positive relationship between IGFBP3 and incidentally elevated triglycerides barely missed statistical significance in women.ConclusionThe present study showed strong cross-sectional associations between IGF1 or IGFBP3 and lipids, whereas no longitudinal relationships were revealed. Therefore, our findings suggest IGF1 and IGFBP3 as a risk marker rather than a risk factor for alterations in lipid metabolism. Further studies are needed to elucidate the mechanisms underlying the association between the GH/IGF axis and lipid metabolism.

In vitro and in vivo models revealed that the somatotropic system exerts central effects on the central nervous system. Disturbances to this system such as in the case of growth hormone deficiency or growth hormone excess, are associated with a wide range of psychiatric disorders. Nonetheless, there is no epidemiological data available regarding the influence of growth hormone and its mediator, insulin-like growth factor I (IGF-I), on depressive disorders. The objective of this study was to investigate whether endogenous IGF-I levels may predict depression in humans. We included 4079 adult subjects from the Study of Health in Pomerania (SHIP), a population-based study with a 5-year follow-up period. The main predictor was the baseline IGF-I value categorized in three levels as10th percentile, between the 10th and the 90th percentile (the reference group) and90th percentile. The outcome measure was the incidence of depressive disorders according to the Composite International Diagnostic-Screener (CID-S). After adjustment for potential confounding variables, females with IGF-I levels below the 10th percentile had a higher incidence of depressive disorders during follow-up (OR 2.70 95% CI 1.38-5.28, p=0.004) compared to females within the reference group (10th-90th percentile). Among males, those with IGF-I levels above the 90th percentile had a higher risk of depressive disorder (OR 3.26 95% CI 1.52-6.98, p=0.002) than those within the 10th-90th percentile. In conclusion we can demonstrate that low IGF-I levels in females and high IGF-I levels in males predict the development of depressive disorders in this general adult population sample.

Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P

Erratum to: https://doi.org/10.1016/j.jalz.2019.01.002

Objective Bone turnover markers (BTMs) reflect the metabolic activity of bone tissue and can be used to monitor osteoporosis therapy. To adequately interpret BTMs, method-specific reference intervals are needed. We aimed to determine reference intervals for serum concentrations of intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP) and carboxy-terminal telopeptide of type I collagen (CTX). Material and methods We established a healthy reference population of 1107 men as well as 382 pre- and 450 postmenopausal women, who participated in the first follow-up of the Study of Health in Pomerania. Serum PINP, BAP and CTX concentrations were measured on the IDS-iSYS Automated System (Immunodiagnostic Systems, Frankfurt am Main, Germany). The reference interval was defined as the central 95% range. We determined age-specific reference intervals for PINP, BAP, and CTX for men by quantile regression. Reference intervals for women were age-independent. Results Reference intervals for men for PINP and CTX decreased with age (25–29 year-old men: PINP 31.1–95.9 ng/mL, CTX 0.12–0.83 ng/mL; 75–79 year-old men: PINP 15.7–68.1 ng/mL, CTX 0.05–0.58 ng/mL). The reference interval for men for BAP did not significantly change with age (25–29 year-old men: 7.4–27.7 ng/mL; 75–79 year-old men: 7.6–24.4 ng/mL). The reference intervals for 30–54 year-old premenopausal women were: PINP 19.3–76.3 ng/mL, BAP 6.0–22.7 ng/mL, and CTX 0.05–0.67 ng/mL. The reference intervals for 50–79 year-old postmenopausal women were: PINP 18.2–102.3 ng/mL, BAP 8.1–31.6 ng/mL, and CTX 0.09–1.05 ng/mL. Conclusion An intensively characterized, large reference population free of bone-related diseases allowed us to determine robust reference intervals for serum concentrations of PINP, BAP and CTX. Our normative data may aid to interpret bone turnover in adult men and pre- and postmenopausal women.

Growth hormone (GH) and its main mediator, insulin-like growth factor I (IGF-I), play a fundamental role in human metabolism. Previous epidemiological studies investigating the association of IGF-I and bone turnover markers (BTMs) yielded conflicting results and were limited by study design or sample size. Therefore, we aimed to investigate the associations between serum levels of IGF-I or the IGF-I/IGF binging protein 3 (IGFBP-3) ratio and levels of BTMs including procollagen type 1 N-terminal propeptide (PINP), C-terminal telopeptides of type 1 collagen (CTX), and bone-specific alkaline phosphatase (BAP).Data from 1463 men and 1481 women who participated in the first follow-up of the Study of Health in Pomerania were used. IGF-I and IGFBP-3 levels were measured using chemiluminescent immunometric assays on an Immulite 2500 analyzer. BTM levels were measured on the IDS-iSYS Multi-Discipline Automated Analyser. Analyses of variance (ANOVA) and quantile regression models were calculated.In men55 years and premenopausal women ANOVA and quantile regression analyses revealed positive associations between IGF-I or even stronger the IGF-I/IGFBP-3 ratio and PINP [per unit increase in IGF-I/IGFBP-3 ratio in men: beta (95%-CI) 2.33 ng/ml (0.91; 3.75), p0.01; women: 3.63 ng/ml (2.31; 4.95), p0.01] or CTX [men: 20.8 ng/l (3.5; 38.0), p = 0.02; women: 12.0 ng/l (-1.2; 25.2), p = 0.07]. Furthermore in postmenopausal women, IGF-I and the IGF-I/IGFBP-3 ratio were inversely related with CTX levels, whereas an inverse U-shaped relation between IGF-I/IGFBP-3 ratio and PINP was found. Regarding BAP, we observed borderline significant associations with IGF-I or the IGF-I/IGFBP-3 ratio in older subjects only.IGF-I levels and particularly free IGF-I, estimated by the IGF-I/IGFBP-3 ratio, are positively related with PINP as a bone formation marker and CTX as a bone resorption marker in healthy adult men younger than 55 years and premenopausal women. In older subjects the found positive as well as negative relations with BTMs have to be further investigated.

Background A previous study showed an inverse association between the insulin-like growth factor I (IGF-I) and the risk of impaired glucose tolerance or diabetes mellitus. Moreover, myocardial infarction patients with high baseline IGF-I levels had a lower risk of diabetes mellitus. These data suggested a protective effect of IGF-I against the development of metabolic syndrome. However, there are no longitudinal data regarding IGF-I and metabolic syndrome. The aim of the present study was to investigate the longitudinal association between IGF-I and metabolic syndrome. Methods Data from the population-based Study of Health in Pomerania, Germany, were used for cross-sectional (n = 3903) and longitudinal (n = 2143) analyses (5-year follow-up). Metabolic syndrome was defined by three or more of the following five components: abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure and elevated nonfasting glucose. Serum IGF-I and IGF binding protein 3 (IGFBP-3) were determined by chemiluminescence immunoassays. Logistic and Poisson regression analyses were performed to determine associations. Results In cross-sectional analyses high IGFBP-3 as well as high and low IGF-I/IGFBP-3 ratio levels were associated with prevalent metabolic syndrome. In longitudinal analyses, the direction of the relation changed: men but not women with high IGF-I or IGF-I/IGFBP-3 ratio levels had an increased, whereas men with low levels had a decreased risk of incident metabolic syndrome. Conclusion In concordance with previous studies, our cross-sectional analyses showed a relation between low IGF-I/IGFBP-3 ratio and the prevalence of metabolic syndrome. In contrast, the longitudinal analyses indicated that a high IGF-I level was a risk marker for incident metabolic syndrome. Copyright © 2013 John Wiley & Sons, Ltd.

Background Besides their prognostic impact blood pressure and peak heart rate are widely used endpoint parameters for incremental exercise tests. Reference equations and ranges on both are sparse. Objective This study aims to describe prediction equations and reference ranges for systolic and diastolic blood pressure as well as for peak heart rate assessed during a symptom limited incremental exercise test based on a population based study – the Study of Health in Pomerania. Design For this purpose, 1708 individuals aged 25–85 years underwent cardiopulmonary exercise testing. Results After exclusion of subjects with cardiopulmonary diseases and antihypertensive medications regression analyses revealed age, sex and body mass index as statistically significant interfering factors. In accordance, prediction equations and reference ranges for blood pressure and peak heart rate with respect to sex, age and BMI have been established. Conclusion This study provides a reliable set of prediction equations for blood pressure and heart rate values at peak exercise, assessed in a general population over a wide age range.

Cases of pancreatitis have been described in connection with the use of exenatide (1), liraglutide (2) and other glucagon-like peptide (GLP)-1 receptor agonists. From these findings, the following hypothesis has been generated: stimulating the GLP-1 receptor with respective agonists has a potential to cause pancreatitis, perhaps chronic pancreatitis, and in the long term, potentially even pancreatic cancer (3–5). Furthermore, in rodents like mice and rats, stimulating the GLP-1 receptor raises cAMP in thyroid C cells, initiates the release of calcitonin, and upon longer-term exposure, is accompanied by C-cell proliferation and the formation of C-cell adenomas and (medullary thyroid) carcinomas (6). Based on these findings, it was hypothesized that GLP-1–derived medications have a potential to cause medullary thyroid carcinoma in humans as well (3,7). It is the purpose of the current review to discuss the evidence in favor and against the hypothesis that GLP-1–based therapies increase cancer risk, specifically the risk for pancreatic and thyroid carcinomas in patients with type 2 diabetes treated with exenatide and sitagliptin. In principle, there could be weak or strong evidence, either in favor of or against, the hypothesis that incretin-based medications can increase the risk for pancreatic, (medullary) thyroid, or other carcinomas. For the purpose of this review, GLP-1–based therapies are GLP-1 receptor agonists such as exenatide, liraglutide, and others or dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin (8). However, almost all available data and quoted studies have specifically examined exenatide and sitagliptin, which have been available for the longest time. The questions of whether certain drugs can cause pancreatitis and whether certain drugs can cause pancreatic carcinoma are interrelated, since chronic pancreatitis increases the risk for pancreatic carcinoma approximately 26-fold compared with subjects not suffering from chronic pancreatitis (9). There is an etiological sequence leading …

Objective: Benefits of replacement therapy in growth hormone deficiency (GHD) are well documented in younger and middle-aged patients. The aim of our investigation was to prove the benefit of GH replacement for patients older than 60 years especially in terms of health-related quality of life (HRQoL) of age as well. Design: Data of 743 consecutively recruited patients (394 men, 349 women) with GHD aged 20 - 49 (n = 606) and 60 - 69 (n = 137) years enrolled from KIMS Germany (Pfizer International Metabolic Database) were compared. Treatment effects over the 12 months dose-finding and the subsequent phase up to three years were analysed using mixed models. Serum insulin-like growth factor I (IGF-I), fasting blood glucose, fasting serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) as well as body mass index (BMI) at baseline and at last visit were studied. HRQoL was assessed using the Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). Results: For both age groups and genders the IGF-I level and standardized IGF-I increased over the dose-finding phase. In women, the overall QoL-AGHDA score at the baseline examination was 8.7 (95% CI: 7.7 - 9.7) and decreased to 6.3 (95% CI: 5.1 - 7.6) at the end of the dose-finding phase (p Conclusion: We could show positive effects of GH replacement on HRQoL in patients older than 60 years of age. Therefore, GH replacement should be considered in elderly GHD adults without difference compared to younger age groups.

Background and objective: The assessment of static lung volumes and airway resistance is a frequently performed diagnostic procedure and considered as an important tool in medical surveillance to detect pulmonary diseases. The objectives of the study are to establish reference equations for body plethysmographic parameters in a representative adult population across a wide age range and to compare the normative values from this sample with previous ones. Methods: Body plethysmography was applied in 1809 participants (885 males) of a cross-sectional, population-based survey (Study of Health in Pomerania). Individuals with cardiopulmonary disorders and/or a pack-year smoking history >10 years and participants with a body mass index >30 kg/m2 were excluded. In total, 686 healthy individuals (275 males) aged 25–85 years were assessed. Results: Prediction equations for both genders were established by quantile regression analysis taking into account the influence of age, height and weight. Conclusions: The study provides a novel set of prediction equations for static lung volumes and airway resistance obtained using body plethysmography. Compared with our findings, existing equations underestimated some normal values. The results emphasize the need for up-to-date reference equations.

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed

Background The bioactive signaling lipid sphingosine-1-phosphate (S1P) is a potential biomarker for cardiovascular disease (CVD). To date, no reference intervals for S1P have been defined. This study aims to establish a reference range for serum S1P in healthy individuals. Methods We determined reference intervals for S1P levels according to gender and age in a sample of 1339 healthy participants of the Study of Health in Pomerania (SHIP)-TREND cohort after exclusion of subjects with CVD, diabetes mellitus, hypertension, metabolic syndrome, elevated liver enzymes, chronic kidney disease stadium III or IV, or body mass index (BMI) > 30 kg/m 2 . Serum S1P was measured by liquid chromatography-tandem mass spectrometry. Results The median age of the participants was 41 (25th; 75th percentile 32; 51) years, 65% were women. The median serum concentration of S1P was 0.804 (0.694; 0.920) μmol/L. No association with gender and age was observed. The overall reference interval was 0.534–1.242 μmol/L (2.5th; 97.5th percentile). Further exclusion of smokers, individuals with BMI > 25 kg/m 2 or elevated lipid levels did not significantly affect median S1P concentrations. Conclusions This study provides reference intervals for serum S1P in healthy individuals. Total serum S1P concentrations vary irrespectively of age, gender, BMI or smoking status.

IGF-1 is known for its various physiological and severe pathophysiological effects on human metabolism; however, underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time, we associated serum IGF-1 levels with multifluid untargeted metabolomics data.Plasma/urine samples of 995 nondiabetic participants of the Study of Health in Pomerania were characterized by mass spectrometry. Sex-specific linear regression analyses were performed to assess the association of IGF-1 and IGF-1/IGF binding protein 3 ratio with metabolites. Additionally, the predictive ability of the plasma and urine metabolome for IGF-1 was assessed by orthogonal partial least squares analyses.We revealed a multifaceted image of associated metabolites with large sex differences. Confirming previous reports, we detected relations between IGF-1 and steroid hormones or related intermediates. Furthermore, various associated metabolites were previously mentioned regarding IGF-1-associated diseases, eg, betaine and cortisol in cardiovascular disease and metabolic syndrome, lipid disorders, and diabetes, or have previously been found to associate with differentiation and proliferation or mitochondrial functionality, eg, phospholipids. bradykinin, fatty acid derivatives, and cortisol, which were inversely associated with IGF-1, might establish a link of IGF-1 with inflammation. For the first time, we showed an association between IGF-1 and pipecolate, a metabolite linked to amino acid metabolism. Our study demonstrates that IGF-1 action on metabolism is tractable, even in healthy subjects, and that the findings provide a solid basis for further experimental/clinical investigation, eg, searching for inflammatory or cardiovascular disease- or metabolic syndrome-associated biomarkers and therapeutic targets.

This study aimed to confirm existing assumptions about the associations of circulating chemerin with inflammatory and metabolic parameters in a large population-based study.Data of 3,986 subjects from the Study of Health in Pomerania were analyzed. Residual method was used to investigate the different associations of visceral (VAT) and subcutaneous adipose tissue (SAT) with serum chemerin levels. Multivariable regression models were applied to examine the association of chemerin with high-sensitivity C-reactive protein, fibrinogen, glucose, glycated hemoglobin, lipid profile, blood pressure, diabetes, dyslipidemia, and hypertension.Positive associations with chemerin were observed for VAT and SAT with a stronger relation found for VAT. After adjustment for waist circumference, increased chemerin levels were related to higher inflammatory cytokines and glycated hemoglobin and an unfavorable lipid profile. Logistic regression revealed positive associations of chemerin with dyslipidemia [highest vs. lowest quartile: odds ratio (OR) 1.56 (95% confidence interval (CI) 1.25-1.94)] and hypertension [OR 1.31 (95% CI 1.03-1.68)].Chemerin levels are significantly linked to inflammation and metabolic syndrome. The majority of the detected associations persisted even after adjustment for waist circumference, suggesting that the relation of chemerin with the analyzed traits cannot be solely explained by an accumulation of adipose tissue.

Abdominal obesity is a major driver for adverse medical conditions. While an interaction between adipose tissue and thyroid function is thought to exist, to our knowledge, no study has examined the effect of thyroid-stimulating hormone (TSH) on visceral adipose tissue (VAT) in a population-based context.We determined an association between serum TSH levels and VAT.A sample of 1,021 female and 956 male adults aged 20-79 years was drawn from registry offices in the cross-sectional, population-based Study of Health in Pomerania Trend (SHIP Trend) in Northeast Germany from 2008 to 2012. Our main exposure was serum TSH levels. Our main outcome was VAT measured using magnetic resonance imaging. The possibly mediating role of leptin on the TSH-VAT association was also assessed.A total of 1,719 participants (87.9%) had serum TSH levels within the reference range. The mean volume of VAT was 5.33 liters for men and 2.83 liters for women. No association between TSH and VAT (β = 0.06, 95% CI: -0.02, 0.14) was observed, and there were no differences detected between sexes. VAT was strongly associated with leptin with a greater effect in women than in men. Leptin was strongly associated with TSH.No association between TSH and VAT was observed. Other biomarkers such as leptin may play a role in the relationship between thyroid function and metabolic risk.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

BACKGROUNDSeveral sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.METHODSWe sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.RESULTSWe found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P = 1.0x10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P = 4.0x10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P = 1.8x10(-3)).CONCLUSIONSASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)

Metabolomic approaches investigate changes in metabolite profiles, which may reflect changes in metabolic pathways and provide information correlated with a specific biological process or pathophysiology. High-resolution (1)H NMR spectroscopy is used to identify metabolites in biofluids and tissue samples qualitatively and quantitatively. This pre-analytical study evaluated the effects of storage time and temperature on (1)H NMR spectra from human urine in two settings. Firstly, to evaluate short time effects probably due to acute delay in sample handling and secondly, the effect of prolonged storage up to one month to find markers of sample miss-handling. A number of statistical procedures were used to assess the differences between samples stored under different conditions, including Projection to Latent Structure Discriminant Analysis (PLS-DA), non-parametric testing as well as mixed effect linear regression analysis. The results indicate that human urine samples can be stored at 10 °C for 24 h or at -80 °C for 1 month, as no relevant changes in (1)H NMR fingerprints were observed during these time periods and temperature conditions. However, some metabolites most likely of microbial origin showed alterations during prolonged storage but without facilitating classification. In conclusion, the presented protocol for urine sample handling and semi-automatic metabolite quantification is suitable for large-scale epidemiological studies.

Summary Obesity is associated with the metabolic syndrome. However, not all obese individuals have cardiovascular risk factors (CVRF). It is not clear how many abdominally obese individuals are free of CVRF and what distinguishes them from the group of obese individuals with CVRF. In this study, we aimed to assess the associated factors and prevalence of abdominal obesity without CVRF. In our cross-sectional analysis, we included n = 4244 subjects from the Study of Health in Pomerania (SHIP), a population-based study and n = 6671 subjects from the Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) study, a representative primary care study in Germany. We defined abdominal obesity by waist-to-height ratio (WHtR) of 0.5 or greater. We assessed how many subjects with abdominal obesity had CVRF based on the definition of the metabolic syndrome. We analysed which conditions were associated with the absence of CVRF in abdominal obesity. In SHIP and DETECT, 2652 (62.5%) and 5126 (76.8%) subjects had a WHtR ≥ 0.5. Among those with a WHtR ≥ 0.5, 9.0% and 13.8% were free of CVRF and 49.9% and 52.7% had at least two CVRF in SHIP and DETECT, respectively. In both studies, after backward elimination, age, male sex, body mass index and high liver enzymes and unemployment were consistently inversely associated with the absence of CVRF. Among abdominally obese subjects, the prevalence of metabolically healthy subjects is low. Conditions consistently associated with the absence of CVRF in abdominal obesity are younger age, female sex, low BMI, and normal liver enzymes, the latter likely reflecting the absence of steatohepatitis.

OBJECTIVE IGF-I has an almost 50% amino acid sequence homology with insulin and elicits nearly the same hypoglycemic response. Studies showed that low and high IGF-I levels are related to impaired glucose tolerance and to a higher risk of type 2 diabetes. The aim of the current study was to evaluate the association between IGF-I level and insulin resistance in a Danish general population. RESEARCH DESIGN AND METHODS Included were 3,354 adults, aged 19–72 years, from the cross-sectional Health2006 study. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to estimate insulin resistance. Serum IGF-I levels were determined by an immunoassay and grouped into quintiles (Q1–Q5). Linear or multinomial logistic regression analyses were performed. RESULTS In the study population, 520 subjects (15.5%) had increased HOMA-IR values above 2.5. After adjustment for age, sex, physical activity, and waist-to-height ratio, a U-shaped association between IGF-I and HOMA-IR was found. Low IGF-I (Q1: odds ratio [OR] 1.65 [95% CI 1.16–2.34], P < 0.01) as well as high IGF-I (Q5: 1.96 [1.38–2.79], P < 0.01) levels were related to a higher odds of increased HOMA-IR values compared with subjects with intermediate (Q3) IGF-I levels. These associations remained statistically significant after the exclusion of subjects with type 2 diabetes and by using the updated computer HOMA2-IR model. CONCLUSIONS Low- and high-normal IGF-I levels are both related to insulin resistance. The biological mechanism of this complex phenomenon has to be elucidated in more detail for future risk stratification.

Several studies in patients with acromegaly or growth hormone (GH) deficiency suggest a stimulatory effect of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis on the renin-angiotensin-aldosterone system (RAAS). We analyzed the association of serum IGF-I with plasma aldosterone and the aldosterone-to-renin ratio in a large sample from the general population. In addition to serum IGF-I levels, we also considered the IGF-I-to-IGF binding protein (IGFBP)-3 ratio. A total of 1 504 men and 1 566 women aged 25-88 were selected from the first follow-up of the population-based Study of Health in Pomerania. Plasma aldosterone and renin concentrations, as well as serum IGF-I and IGFBP-3 levels were determined with immunoassays. Analyses of variance and linear regression analyses were performed. We found positive associations between serum IGF-I or the IGF-I/IGFBP-3 ratio with plasma aldosterone in women but not in men. Plasma aldosterone levels increased by 2.91 ng/l per IGF-I standard deviation (SD) and by 2.17 ng/l per IGF-I/IGFBP-3 SD. The associations remained significant after exclusion of subjects taking RAAS-altering medication and of subjects with serum IGF-I levels and aldosterone-to-renin ratios outside the reference range. We conclude that, serum IGF-I and the IGF-I/IGFBP-3 ratio are associated with plasma aldosterone levels in women but not in men from the general population.

Objective: Previous studies reported associations between insulin-like growth factor I (IGF-I) serum concentration and cardiac morbidity and mortality, but the association between IGF-I serum concentration and cardiac repolarization has not been investigated in a population-based study so far. Therefore, we analyzed the impact of IGF-I concentrations on QTc, QT and RR intervals in two population based studies, The Study of Health in Pomerania (SHIP) and the Rotterdam Study. Design: 457 individuals from SHIP and 155 individuals from the Rotterdam Study older than 55 years and without cardiovascular diseases and a left ventricular hypertrophy were investigated. IGF-I was determined by automated two-site chemiluminescence immunoassays and electrocardiograms were recorded by an ACTA electrocardiograph at a sampling frequency of 500 Hz. The association of IGF-I with QTc, QT and RR intervals was investigated by multivariable linear regression analyses adjusted for age, gender, diabetes mellitus, myocardial infarction, hypertension, body mass index, serum potassium and calcium in both studies separately and in pooled analysis. Results: There were no significant associations between log-transformed IGF-I and QTc interval in the single populations, whereas a significant inverse association was detectable in the pooled population (beta, -15.6; 95%-confidence interval, -25.7, -5.5). The QTc interval was significantly higher in the first tertile of IGF-I compared to the third tertile (beta, 5.4; 95%-confidence interval, 9.5-1.3) in the pooled analysis. Conclusion: The inverse association between IGF-I serum concentrations and QTc interval in our study is suggestive of a higher risk for cardiac arrhythmias and thus might provide additional evidence for increased cardiovascular mortality in subjects with low IGF-I secretion. (C) 2011 Elsevier Ltd. All rights reserved.

Chronological age is one of the most important risk factors for adverse clinical outcome. Still, two individuals at the same chronological age could have different biological aging states, leading to different individual risk profiles. Capturing this individual variance could constitute an even more powerful predictor enhancing prediction in age-related morbidity. Applying a nonlinear regression technique, we constructed a metabonomic measurement for biological age, the metabolic age score, based on urine data measured via (1)H NMR spectroscopy. We validated the score in two large independent population-based samples by revealing its significant associations with chronological age and age-related clinical phenotypes as well as its independent predictive value for survival over approximately 13 years of follow-up. Furthermore, the metabolic age score was prognostic for weight loss in a sample of individuals who underwent bariatric surgery. We conclude that the metabolic age score is an informative measurement of biological age with possible applications in personalized medicine.

To investigate three-echo T2*-corrected Dixon magnetic resonance imaging (MRI) for noninvasively estimating hepatic fat content (HFC) compared with biopsy.One hundred patients (50 men, 50 women; mean age, 57.7±14.2 years) underwent clinically indicated liver core biopsy (102 valid tissue samples) and liver MRI 24 to 72 hours later. MRI was performed at 1.5T (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany) using Dixon imaging with T2* correction (work in progress, WIP-432.rev.1, Siemens Healthcare). An ultrafast breath-hold three-echo 3D-gradient echo sequence with TR/TE1/TE2/TE3 of 11/2.4/4.8/9.6 milliseconds, and online calculation of T2*-corrected water images (signal intensities of water [SIW]), fat images (SIF), and fat content map (SIFAT=10×SIF/(SIW+SIF)) was used. SIs of the calculated fat content map (SIFAT) were verified using the histologically quantified HFC (HFC(path)). Spearman correlation for HFC(path) and SIFAT was calculated. Stage of fibrosis, hepatic iron content, and patterns of liver fat (macrovesicular, microvesicular, mixed) and their influence on predicting HFC by MRI were determined.Correlation between SIFAT and HFC(path) was rspearman=0.89. Agreement between HFC predicted by MRI and HFC(path) calculated by nonlinear saturation-growth regression was rspearman=0.89. Kruskal-Wallis analysis revealed no significant difference for SIFAT across fibrosis grades (P=0.90) and liver iron content (P=0.76). Regarding the cellular architecture of liver fat, the microvesicular pattern showed lower mean ranks in SI than macrovesicular and mixed patterns (P=0.01).T2*-corrected Dixon MRI is a noninvasive tool for estimating HFC, showing excellent correlation with liver biopsy without being limited by liver iron content and fibrosis/cirrhosis.

Summary Objective Prolactin (PRL) is involved in immune regulation and may contribute to an atherogenic phenotype. Previous results on the association of PRL with inflammatory biomarkers have been conflicting and limited by small patient studies. Therefore, we used data from a large population-based sample to assess the cross-sectional associations between serum PRL concentration and high-sensitivity C-reactive protein (hsCRP), fibrinogen, interleukin-6 (IL-6), and white blood cell (WBC) count. Design and Population From the population-based Study of Health in Pomerania (SHIP), a total of 3744 subjects were available for the present analyses. Methods and Measurements PRL and inflammatory biomarkers were measured. Linear and logistic regression models adjusted for age, sex, body-mass-index, total cholesterol and glucose were analysed. Results Multivariable linear regression models revealed a positive association of PRL with WBC. Multivariable logistic regression analyses showed a significant association of PRL with increased IL-6 in non-smokers [highest vs lowest quintile: odds ratio 1·69 (95% confidence interval 1·10–2·58), P = 0·02] and smokers [OR 2·06 (95%-CI 1·10–3·89), P = 0·02]. Similar results were found for WBC in non-smokers [highest vs lowest quintile: OR 2·09 (95%-CI 1·21–3·61), P = 0·01)] but not in smokers. Linear and logistic regression analyses revealed no significant associations of PRL with hsCRP or fibrinogen. Conclusions Serum PRL concentrations are associated with inflammatory biomarkers including IL-6 and WBC, but not hsCRP or fibrinogen. The suggested role of PRL in inflammation needs further investigation in future prospective studies.

Summary Objective Previous studies detected associations between lower insulin-like growth factor I (IGF-I) levels and increased risk of congestive heart failure or ischaemic heart disease. The aim of the present study was to assess the association of IGF-I and its binding protein 3 (IGFBP-3) with the carotid intima–media thickness (IMT) as marker of asymptomatic cardiovascular disease. Design and population From the population-based Study of Health in Pomerania (SHIP), a total of 2286 participants aged 45 years or older with readable ultrasound of the carotid arteries were available for the present analyses. Methods and measurements Serum IGF-I and IGFBP-3 levels were categorized into three groups (low, moderate, high) according to the sex-specific 10th and 90th percentile. Analyses of variance (anova) and logistic regression analyses adjusted for age, waist circumference, diabetes, hypertension and creatinine clearance were performed. Results After adjusting for confounding factors, IGF-I and the IGF-I/IGFBP-3 ratio were positively related to IMT in anova. Logistic regression analyses confirmed these findings and showed that high IGF-I levels, a high IGF-I/IGFBP-3 ratio and low IGFBP-3 levels were associated to higher odds of increased IMT. Conclusion In conclusion, high IGF-I or high IGF-I/IGFBP-3 ratio values and low IGFBP-3 levels are associated with increased IMT. Therefore, systemic levels of the IGF axis or alterations in the balance of its components are associated with subclinical atherosclerotic disease.

We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10(-19) to 2.1 × 10(-182). Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria.

Objective Surveys frequently deviate from simple random sampling through the use of unequal probability sampling, stratified sampling, and multistage sampling. This work uses a survey of public health to systematically illustrate the effects of incompletely accounting for strata, clustering, and weights. Study Design and Setting Data analysis was based on the Study of Health in Pomerania ( n =4,308, 20–79 years), a two-stage regional survey with high sampling fractions at the first stage. Effects of survey design features comprising weights, stratification, clustering, and finite population correction on point and variance estimates of lifestyle indicators and clinical parameters were assessed. Results Misspecifications of the survey design substantially affected both the point estimates of health characteristics and their standard errors (SEs). The strongest bias in SEs concerned the omission of the second sampling stage. Ignoring the sampling design led to minor differences in variance estimates from the complete setup. Weighting predominantly affected point estimates of lifestyle factors. Conclusion A partial misspecification of survey design elements may bias variance estimates severely and is sometimes even more harmful compared with completely neglecting design elements. If subgroups are sampled at different rates, weighting is of particular relevance with regard to prevalence estimates of lifestyle indicators.

Summary Background Spirometry is a frequently performed lung function test and an important tool in medical surveillance examinations of pulmonary diseases. The interpretation of lung function relies on the comparison to reference values derived from a healthy population. The study aim was to compare the lung function data of three representative population-based German studies (Study of Health in Pomerania [SHIP-1], Cooperative Health Research in the Region of Augsburg [KORA-S3] and European Community Respiratory Health Survey Erfurt [ECRHS-I Erfurt]) with existing European spirometry reference values and to establish a new set of comprehensive German prediction equations. Methods Spirometry was performed in 4133 participants of three population-based surveys using almost identical standardised methods. Current and former smokers, subjects with cardiopulmonary disorders or on medication with potential influence on lung function were excluded. Sex specific prediction equations were established by quantile regression analyses. Comparison was performed to existing European reference values. Results The healthy reference sample consisted of 1302 (516 male) individuals, aged 20–80 years. Sex specific comprehensive prediction equations adjusted for age and height are provided. Significant differences were found in comparison to previous studies with pronounced lower values of the current population if applying historic prediction equations. Conclusion The results contribute to the interpretation of lung function examination in providing a comprehensive set of spirometry reference values obtained in a large number of healthy volunteers. Whereas the differences in between the investigated studies are negligible, striking divergence was detected in comparison to historic and recent European spirometry prediction values.

Objective: To evaluate the treatment effects of long-term growth hormone (GH) replacement therapy in adults with GH deficiency (GHD) who were followed in KIMS Germany (Pfizer International Metabolic Database), a national surveillance study. Design: The analysis was performed using baseline and long-term data (range: 4-10. years) of 440 consecutively documented patients (216 women and 224 men) with GHD, aged 20 to 49. years, enrolled in KIMS Germany. Serum insulin-like growth factor I (IGF-I), fasting blood glucose, fasting serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) as well as body mass index (BMI), waist circumference (WC) and hip circumference (HC) at baseline and at last visit were studied. Furthermore, QoL-AGHDA score was determined to assess quality-of-life (QoL). Results: The mean dose of GH over all years was 0.41. mg per day in women and 0.37. mg per day in men. IGF-I and IGF-I SDS levels (standard deviation score) increased significantly (p < 0.001) during GH treatment. The QoL-AGHDA score decreased significantly (p < 0.001), indicating long-lasting improvement in QoL. In total cholesterol, LDL-C and fasting blood glucose, no significant changes were found. Only six patients developed type 2 diabetes during follow-up. Females and males similarly increased significantly in BMI, WC and HC. During GH treatment, recurrences of pituitary or central nervous system tumours or further de novo neoplasia were reported in 6 or 11 patients, respectively. The number of the most frequently reported GH treatment-associated adverse events was low. Conclusion: These observational data show long-term beneficial effects of GH replacement therapy on QoL and show no significant effects on total cholesterol, LDL-C or BMI, WC and HC. Additionally, our data indicate that GH replacement therapy in adults is well tolerated.

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combined potential for improved mortality risk stratification is unknown. Methods: We used data of 1,822 men from the population-based Study of Health in Pomerania followed- up for 9.9 years (median). The direct effects of kidney dysfunction (estimated glomerular filtration rate 2), albuminuria (urinary albumin-creatinine ratio ≧2.5 mg/mmol) and their combination (CKD) on all-cause and cardiovascular mortality were analyzed using multivariable Cox regression models. Serum TT concentrations below the age-specific 10th percentile (by decades) were considered low and were used for further risk stratification. Results: Kidney dysfunction (hazard ratio, HR, 1.40; 95% confidence interval, CI, 1.02–1.92), albuminuria (HR, 1.38; 95% CI, 1.06–1.79), and CKD (HR, 1.42; 95% CI, 1.09–1.84) were associated with increased all-cause mortality risk, while only kidney dysfunction (HR, 2.01; 95% CI, 1.21–3.34) was associated with increased cardiovascular mortality risk after multivariable adjustment. Men with kidney dysfunction and low TT concentrations were identified as high-risk individuals showing a more than 2-fold increased all-cause mortality risk (HR, 2.52; 95% CI, 1.08–5.85). Added to multivariable models, nonsignificant interaction terms suggest that kidney dysfunction and low TT are primarily additive rather than synergistic mortality risk factors. Conclusion: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome.

Background Insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) are central mediators of endocrine effects of growth hormone and there is increasing evidence for an association with muscle strength and exercise capacity. The aim of the present study was to clarify the possible association of circulating IGF-I and IGFBP-3 concentrations and exercise capacity in a general adult population. Materials and methods From the Study of Health in Pomerania (SHIP) 1332 subjects aged 25 to 85 years participated in a standardised symptom limited cardiopulmonary exercise test on a bicycle. Exercise capacity was characterized by oxygen uptake at anaerobic threshold (VO 2 @AT), peak exercise (peakVO 2 ), oxygen pulse and maximum power output at peak exertion. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity and smoking were performed. Results At peak exercise performance, in women IGF-I showed significant associations to peakVO 2 and maximum power output, IGF-I/IGFBP-3 ratio was associated with maximum power output. In men, this association was not consistently reproducible. Neither IGF-I nor IGFBP-3 did reveal any association to VO 2 @AT in both genders. Conclusion Serum IGF-I concentrations are associated with peak exercise capacity in healthy women, but not in men over a wide range in ages, body sizes and activity scores.

Iron deficiency is the most frequent deficiency disease and parameters of iron metabolism appear to be linked to major metabolic and cardiovascular diseases. We screened a large set of small molecules in plasma for associations with iron status among apparently healthy subjects to elucidate subclinical profiles which may provide a link between iron status and onset of diseases. Based on mass spectrometry and nuclear magnetic resonance spectroscopy we determined 613 plasma metabolites and lipoprotein subfractions among 820 apparently healthy individuals. Associations between ferritin, transferrin, haemoglobin and myoglobin and metabolite levels were tested by sex-specific linear regression analyses controlling for common confounders. Far more significant associations in women (82 out of 102) compared to men became obvious. The majority of the metabolites associated with serum ferritin and haemoglobin in women comprising fatty acid species, branched-chain amino acid catabolites and catabolites of heme. The latter was also obvious among men. Positive associations between serum transferrin and VLDL and IDL particle measures seen in women were observed in men with respect to serum ferritin. We observed a sexual-dimorphic fingerprint of surrogates of iron metabolism which may provide a link for the associations between those parameters and major metabolic and cardiovascular disease.

There is increasing evidence suggesting that low total testosterone concentration is associated with incident type 2 diabetes mellitus (T2DM) in men. The aim of this study was to evaluate the association between total testosterone and incident T2DM in a large population-based cohort.Of 2117 men at baseline, 1589 were followed up 5 years later. Low total testosterone concentration at baseline determined by10th percentile (10-year age-strata) were used as a risk factor for incident T2DM at follow-up. To evaluate for potential non-response bias, drop out weights were used in sensitivity analysis.From 1339 men eligible for analyses, 68 (5.1%) developed T2DM. Men with low total testosterone concentration had an increased risk of developing T2DM (odds ratio [OR] 3.4, 95% CI 1.9-6.1), even after adjustment for age, waist circumference and smoking, OR 3.0; (95% CI 1.6-5.7). Recalculated weighted models revealed almost identical estimates indicating no relevant non-response bias.Our prospective findings suggest that low total testosterone concentration is associated with incident T2DM in men and might represent a biomarker that might causally be involved in the risk of T2DM. This underlines the importance of measuring total testosterone in men as the predominant male sex hormone.

Testosterone exerts a widespread pattern of effects on metabolism and body composition, and interest is gaining in its correlation with physical fitness. The main focus of our study was to investigate the association of total serum testosterone and sex hormone–binding globulin (SHBG) levels on exercise capacity and maximal power output in men using a cross-sectional, population-based adult cohort. From the Study of Health in Pomerania (SHIP), 624 men age 25 to 85 years who underwent a standardized progressive incremental exercise protocol on a cycle ergometer were included in the analyses. Exercise capacity was characterized by oxygen uptake at anaerobic threshold (V′O2 at θL) and peak exercise (V′O2peak) as well as maximal power output at peak exertion. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity, and smoking were performed. Further, linear regression analyses with cubic splines and sensitivity analyses were undertaken. At peak exercise performance, testosterone and SHBG levels showed no associations with V′O2peak, V′O2 at θL as well as maximal power output, even after controlling for confounding factors including age, body mass index, physical activity, and smoking. An adverse association between the free testosterone index and V′O2 at θL was found. Linear regression analyses with cubic splines did not change the main results. In conclusion, this is the first study focusing on the association of total serum testosterone and SHBG on exercise capacity and physical performance in healthy volunteers based on a large-scale population-based study. After adjustment for relevant influencing factors, neither total serum testosterone nor SHBG levels had any interference with peak exercise capacity, aerobic exercise capacity, or maximal power output in men.

Risk alleles of the fat mass- and obesity-associated gene (FTO) are related not only to increased body mass index (BMI) values but also to mortality. It was speculated that cellular effects of the FTO gene affect most organs, especially their ability to maintain or regenerate proper function when afflicted by various diseases. FTO is highly expressed in the hypothalamus and also in the pituitary gland. The decrease in growth hormone (GH) secretion is known to cause a decrease in lean body mass in older subjects.We hypothesized an association of rs9926289 with insulin-like growth factor (IGF)-I.Cross-sectional data from the Study of Health in Pomerania, a population-based study in the northeastern part of Germany, were used.For the final analyses, 3882 subjects aged 20-79 years were available.Continuous IGF-I, low IGF-I according to clinically meaningful age- and gender-specific reference values, and BMI were used as outcome measures.Over all age groups, a statistically significant relationship between FTO and IGF-I was found. In subjects younger than 55 years of age, homozygous carriers of the FTO risk allele exhibited lower serum IGF-I levels adjusted for 5-year age groups, gender and IGF-I binding protein 3 levels (linear regression, coefficient±s.e. for FTO AA genotype:-8.6±2.8; P=0.002). Further adjustments for obesity and diabetes did not suspend this association (coefficient:-7.8; P=0.005). As expected, the FTO AA genotype effect on BMI was reduced from 0.76 to 0.62 kg m(-2) by including IGF-I. No relationship between FTO and IGF-I levels was found in subjects aged 55 years or older (-2.7±2.4; P=0.260 for FTO AA genotype adjusted for age, gender and IGF-I binding protein 3 levels).We propose that the GH-IGF-I axis is a mediator for the relationship between FTO and BMI.

There is increasing evidence that urinary albumin excretion, even when below the accepted threshold values for normal excretion, may have significant impact on future cardiovascular risks. To further define this, a total of 1086 patients, aged 45 years and older from the population-based, longitudinal 'Study of Health in Pomerania' were evaluated. Patients had echocardiographic analysis at baseline and 5-year follow-up, and were grouped into quartiles according to their baseline urinary albumin-to-creatinine ratio. At baseline, left ventricular mass in the first three quartiles was similar; however, the fourth quartile was significantly elevated and further increased over the 5-year follow-up. In the first quartile, the albumin-to-creatinine ratio and left ventricular mass did not significantly change over 5 years. In the second and third quartiles, the left ventricular mass progressively increased and was significantly correlated with the albumin-to-creatinine ratio. In multivariable analysis, this association was independent of other common cardiovascular risk factors and applicable to both genders. Our study found that the urinary albumin-to-creatinine ratio, even below the current threshold for definition of microalbuminuria, is significantly associated with increased left ventricular mass.