Nele Friedrich

Cohort Profile: The Study of Health in Pomerania

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

The Predictive Value of Different Measures of Obesity for Incident Cardiovascular Events and Mortality

CONTEXT To date, it is unclear which measure of obesity is the most appropriate for risk stratification. OBJECTIVE The aim of the study was to compare the associations of various measures of obesity with incident cardiovascular events and mortality. DESIGN AND SETTING We analyzed two German cohort studies, the DETECT study and SHIP, including primary care and general population. PARTICIPANTS A total of 6355 (mean follow-up, 3.3 yr) and 4297 (mean follow-up, 8.5 yr) individuals participated in DETECT and SHIP, respectively. INTERVENTIONS We measured body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) and assessed cardiovascular and all-cause mortality and the composite endpoint of incident stroke, myocardial infarction, or cardiovascular death. RESULTS In both studies, we found a positive association of the composite endpoint with WHtR but not with BMI. There was no heterogeneity among studies. The relative risks in the highest versus the lowest sex- and age-specific quartile of WHtR, WC, WHR, and BMI after adjustment for multiple confounders were as follows in the pooled data: cardiovascular mortality, 2.75 (95% confidence interval, 1.31-5.77), 1.74 (0.84-3.6), 1.71 (0.91-3.22), and 0.74 (0.35-1.57), respectively; all-cause mortality, 1.86 (1.25-2.76), 1.62 (1.22-2.38), 1.36 (0.93-1.69), and 0.77 (0.53-1.13), respectively; and composite endpoint, 2.16 (1.39-3.35), 1.59 (1.04-2.44), 1.49 (1.07-2.07), and 0.57 (0.37-0.89), respectively. Separate analyses of sex and age groups yielded comparable results. Receiver operating characteristics analysis yielded the highest areas under the curve for WHtR for predicting these endpoints. CONCLUSIONS WHtR represents the best predictor of cardiovascular risk and mortality, followed by WC and WHR. Our results discourage the use of the BMI.

A genome-wide association study of metabolic traits in human urine

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.

Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data

CONTEXT Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

Reference Intervals for Insulin-like Growth Factor-1 (IGF-I) From Birth to Senescence: Results From a Multicenter Study Using a New Automated Chemiluminescence IGF-I Immunoassay Conforming to Recent International Recommendations

CONTEXT Measurement of IGF-I is a cornerstone in diagnosis and monitoring of GH-related diseases, but considerable discrepancies exist between analytical methods. A recent consensus conference defined criteria for validation of IGF-I assays and for establishment of normative data. OBJECTIVES Our objectives were development and validation of a novel automated IGF-I immunoassay (iSYS; Immunodiagnostic Systems) according to international guidelines and establishment of method-specific age- and sex-adjusted reference intervals and analysis of their robustness. SETTING AND PARTICIPANTS We conducted a multicenter study with samples from 12 cohorts from the United States, Canada, and Europe including 15 014 subjects (6697 males and 8317 females, 0-94 years of age). MAIN OUTCOME MEASURES We measured concentrations of IGF-I as determined by the IDS iSYS IGF-I assay. RESULTS A new IGF-I assay calibrated against the recommended standard (02/254) and insensitive to the 6 high-affinity IGF binding proteins was developed and rigorously validated. Age- and sex-adjusted reference intervals derived from a uniquely large cohort reflect the age-related pattern of IGF-I secretion: a decline immediately after birth followed by an increase until a pubertal peak (at 15 years of age). Later in life, values decrease continuously. The impact of gender is small, although across the lifespan, women have lower mean IGF-I concentrations. Geographical region, sampling setting (community or hospital based), and rigor of exclusion criteria in our large cohort did not affect the reference intervals. CONCLUSIONS Using large cohorts of well-characterized subjects from different centers allowed construction of robust reference ranges for a new automated IGF-I assay. The strict adherence to recent consensus criteria for IGF-I assays might facilitate clinical application of the results.

Mortality and serum insulin-like growth factor (IGF)-I and IGF binding protein 3 concentrations

BACKGROUND Previous studies provided conflicting results regarding the association of serum IGF-I or IGF-binding protein-3 (IGFBP-3) and mortality. The aim of this study was to assess the relation of IGF-I and IGFBP-3 levels with mortality from all causes, cardiovascular disease (CVD), and cancer in a prospective population-based study. METHODS From the Study of Health in Pomerania (SHIP) 1988 men and 2069 women aged 20-79 yr were followed up on average 8.5 yr. Causes of deaths were coded according to the International Classification of Diseases, 10th revision. Serum IGF-I and IGFBP-3 levels were determined by chemiluminescence immunoassays and categorized into three groups (low, normal, high) according to the sex- and age-specific 10th and 90th percentiles. RESULTS Adjusted analyses revealed that men with low but not high IGF-I levels had an almost 2-fold higher risk of all-cause mortality [hazard ratio (HR) 1.92 (95% confidence interval [CI] 1.35; 2.73)], CVD mortality [HR 1.92 (95% CI 1.00; 3.71)], and cancer mortality [HR 1.85 (95% CI 1.00; 3.45)] compared with men with normal IGF-I levels. In women, no association between IGF-I and mortality was found. Moreover, low IGFBP-3 levels were associated with higher all-cause mortality in men [HR 1.87 (95% CI 1.31; 2.64)] and women [HR 1.63 (95% CI 0.96; 2.76)]. CONCLUSIONS The present study found inverse associations between IGF-I or IGFBP-3 levels and mortality from all causes, CVD, or cancer in men and between IGFBP-3 and all-cause mortality in women.

The Association Between IGF-I and Insulin Resistance A general population study in Danish adults

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.

Do GLP-1–Based Therapies Increase Cancer Risk?

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 …

Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies

OBJECTIVE The prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30-79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects. METHODS Data were obtained from the first follow-ups of the population-based study of health in Pomerania (SHIP; n=1392) and the cooperative health research in the region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies.Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC. RESULTS The frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A-C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects. CONCLUSIONS A maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients.

Reference Ranges for Serum Dehydroepiandrosterone Sulfate and Testosterone in Adult Men

Dehydroepiandrosterone (DHEA) is the main adrenal androgen, which mostly exists in a sulfated version (DHEAS). Both DHEA and DHEAS are metabolic intermediates in the biosynthesis of the male sex hormone testosterone. In men, testosterone is involved in the regulation of fertility, libido, and muscle mass and is valuable for the assessment of gonadal, adrenal, and pituitary function and for the diagnosis of hypogonadism. The objective of the present study was to calculate age-specific reference ranges for serum DHEAS and serum testosterone using 1) linear regression and the mean +/- 1.96 standard deviation concept and 2) quantile regression. From the cross-sectional Study of Health in Pomerania a total of 1078 men aged 20-79 years were included in the analyses. Serum DHEAS and testosterone levels were quantified using IMMULITE 2500 immunoassays. Linear and quantile regression were performed to calculate age-specific reference ranges. Both statistical methods generated different results: The reference ranges based on linear regression identified 17 men (1.6%) with DHEAS levels and 45 men (4.2%) with serum testosterone levels outside the reference range. Using quantile regression, 54 men (5.0%) and 50 men (4.6%) with serum DHEAS and testosterone levels outside the range were detected, respectively. The present study established age-specific reference ranges for serum DHEAS and testosterone levels for men. Quantile regression should be preferred to calculate reference ranges; a better concordance with original data is possible because no distribution assumption is required and the robustness against outliers is given.