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1. Relation of IGF-I with subclinical cardiovascular markers including intima-media thickness, left ventricular mass index and NT-proBNP

Author

Maximilian Eichner, Henri Wallaschofski, Ulf Schminke, Henry Völzke, Marcus Dörr, Stephan B Felix, Matthias Nauck, and Nele Friedrich

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Objective: Several studies revealed relations between low or high insulin -like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms be hind these associations are still unknown. Design: The study aimed to explore the relations between IGF-I and cha nges in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ve ntricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Methods: Longitudinal data of the population-based cohort Study of Heal th in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on ec hocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular conf ounders were performed. Results: Statistical analyses demonstrated relations between low baseli ne IGF-I levels (beta for ΔIMT per s.d. increase −0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta −0.045 (0.012)) and a long-term IMT increase. No associations be tween IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline I GF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IG FBP-3 ratio with an increase in NT-proBNP were found. Conclusions: The study detected significant relations between IGF-I and long -term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities.

Published
2019
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2. The Membrane Transporter OAT7 (SLC22A9) Is Not a Susceptibility Factor for Osteoporosis in Europeans

Author

Anne T. Nies, Stefan Weiss, Elke Schaeffeler, Anke Hannemann, Uwe Völker, Henri Wallaschofski, and Matthias Schwab

Subjects
estrone sulfate transporter, SLC22A9, osteoporosis, human association studies, sex steroids, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

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 SLC22A9 gene have been associated with osteoporosis in Korean females. We had recently shown that SLC22A9, encoding organic anion transporter 7 (OAT7), is an uptake transporter of estrone sulfate and identified several genetic variants in Europeans leading to functional consequences in vitro. We therefore hypothesized that SLC22A9 genetic variants may contribute to the pathophysiology of osteoporosis in Europeans. To test this hypothesis, we examined the associations of SLC22A9 variants with bone quality, fractures, and bone turnover markers. We genotyped SLC22A9 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 SLC22A9 variants and bone quality, fractures, and bone turnover markers. Our results indicate that single genetic SLC22A9 variants do not have a major impact on osteoporosis risk prediction in Europeans, yet findings need to be replicated in larger-scale studies.

Published
2020
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3. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Xia Jiang, Paul F. O’Reilly, Hugues Aschard, Yi-Hsiang Hsu, J. Brent Richards, Josée Dupuis, Erik Ingelsson, David Karasik, Stefan Pilz, Diane Berry, Bryan Kestenbaum, Jusheng Zheng, Jianan Luan, Eleni Sofianopoulou, Elizabeth A. Streeten, Demetrius Albanes, Pamela L. Lutsey, Lu Yao, Weihong Tang, Michael J. Econs, Henri Wallaschofski, Henry Völzke, Ang Zhou, Chris Power, Mark I. McCarthy, Erin D. Michos, Eric Boerwinkle, Stephanie J. Weinstein, Neal D. Freedman, Wen-Yi Huang, Natasja M. Van Schoor, Nathalie van der Velde, Lisette C. P. G. M. de Groot, Anke Enneman, L. Adrienne Cupples, Sarah L. Booth, Ramachandran S. Vasan, Ching-Ti Liu, Yanhua Zhou, Samuli Ripatti, Claes Ohlsson, Liesbeth Vandenput, Mattias Lorentzon, Johan G. Eriksson, M. Kyla Shea, Denise K. Houston, Stephen B. Kritchevsky, Yongmei Liu, Kurt K. Lohman, Luigi Ferrucci, Munro Peacock, Christian Gieger, Marian Beekman, Eline Slagboom, Joris Deelen, Diana van Heemst, Marcus E. Kleber, Winfried März, Ian H. de Boer, Alexis C. Wood, Jerome I. Rotter, Stephen S. Rich, Cassianne Robinson-Cohen, Martin den Heijer, Marjo-Riitta Jarvelin, Alana Cavadino, Peter K. Joshi, James F. Wilson, Caroline Hayward, Lars Lind, Karl Michaëlsson, Stella Trompet, M. Carola Zillikens, Andre G. Uitterlinden, Fernando Rivadeneira, Linda Broer, Lina Zgaga, Harry Campbell, Evropi Theodoratou, Susan M. Farrington, Maria Timofeeva, Malcolm G. Dunlop, Ana M. Valdes, Emmi Tikkanen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Mika Kähönen, Olli T. Raitakari, Vera Mikkilä, M. Arfan Ikram, Naveed Sattar, J. Wouter Jukema, Nicholas J. Wareham, Claudia Langenberg, Nita G. Forouhi, Thomas E. Gundersen, Kay-Tee Khaw, Adam S. Butterworth, John Danesh, Timothy Spector, Thomas J. Wang, Elina Hyppönen, Peter Kraft, and Douglas P. Kiel

Subjects
Science
Abstract

Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.

Published
2018
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4. Sex-specific metabolic profiles of androgens and its main binding protein SHBG in a middle aged population without diabetes

Author

Uwe Piontek, Henri Wallaschofski, Gabi Kastenmüller, Karsten Suhre, Henry Völzke, Kieu Trinh Do, Anna Artati, Matthias Nauck, Jerzy Adamski, Nele Friedrich, and Maik Pietzner

Subjects
Medicine, Science
Abstract

Abstract 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.

Published
2017
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5. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Yingchang Lu, Felix R. Day, Stefan Gustafsson, Martin L. Buchkovich, Jianbo Na, Veronique Bataille, Diana L. Cousminer, Zari Dastani, Alexander W. Drong, Tõnu Esko, David M. Evans, Mario Falchi, Mary F. Feitosa, Teresa Ferreira, Åsa K. Hedman, Robin Haring, Pirro G. Hysi, Mark M. Iles, Anne E. Justice, Stavroula Kanoni, Vasiliki Lagou, Rui Li, Xin Li, Adam Locke, Chen Lu, Reedik Mägi, John R. B. Perry, Tune H. Pers, Qibin Qi, Marianna Sanna, Ellen M. Schmidt, William R. Scott, Dmitry Shungin, Alexander Teumer, Anna A. E. Vinkhuyzen, Ryan W. Walker, Harm-Jan Westra, Mingfeng Zhang, Weihua Zhang, Jing Hua Zhao, Zhihong Zhu, Uzma Afzal, Tarunveer Singh Ahluwalia, Stephan J. L. Bakker, Claire Bellis, Amélie Bonnefond, Katja Borodulin, Aron S. Buchman, Tommy Cederholm, Audrey C. Choh, Hyung Jin Choi, Joanne E. Curran, Lisette C. P. G. M. de Groot, Philip L. De Jager, Rosalie A. M. Dhonukshe-Rutten, Anke W. Enneman, Elodie Eury, Daniel S. Evans, Tom Forsen, Nele Friedrich, Frédéric Fumeron, Melissa E. Garcia, Simone Gärtner, Bok-Ghee Han, Aki S. Havulinna, Caroline Hayward, Dena Hernandez, Hans Hillege, Till Ittermann, Jack W. Kent, Ivana Kolcic, Tiina Laatikainen, Jari Lahti, Irene Mateo Leach, Christine G. Lee, Jong-Young Lee, Tian Liu, Youfang Liu, Stéphane Lobbens, Marie Loh, Leo-Pekka Lyytikäinen, Carolina Medina-Gomez, Karl Michaëlsson, Mike A. Nalls, Carrie M. Nielson, Laticia Oozageer, Laura Pascoe, Lavinia Paternoster, Ozren Polašek, Samuli Ripatti, Mark A. Sarzynski, Chan Soo Shin, Nina Smolej Narančić, Dominik Spira, Priya Srikanth, Elisabeth Steinhagen-Thiessen, Yun Ju Sung, Karin M. A. Swart, Leena Taittonen, Toshiko Tanaka, Emmi Tikkanen, Nathalie van der Velde, Natasja M. van Schoor, Niek Verweij, Alan F. Wright, Lei Yu, Joseph M. Zmuda, Niina Eklund, Terrence Forrester, Niels Grarup, Anne U. Jackson, Kati Kristiansson, Teemu Kuulasmaa, Johanna Kuusisto, Peter Lichtner, Jian'an Luan, Anubha Mahajan, Satu Männistö, Cameron D. Palmer, Janina S. Ried, Robert A. Scott, Alena Stancáková, Peter J. Wagner, Ayse Demirkan, Angela Döring, Vilmundur Gudnason, Douglas P. Kiel, Brigitte Kühnel, Massimo Mangino, Barbara Mcknight, Cristina Menni, Jeffrey R. O'Connell, Ben A. Oostra, Alan R. Shuldiner, Kijoung Song, Liesbeth Vandenput, Cornelia M. van Duijn, Peter Vollenweider, Charles C. White, Michael Boehnke, Yvonne Boettcher, Richard S. Cooper, Nita G. Forouhi, Christian Gieger, Harald Grallert, Aroon Hingorani, Torben Jørgensen, Pekka Jousilahti, Mika Kivimaki, Meena Kumari, Markku Laakso, Claudia Langenberg, Allan Linneberg, Amy Luke, Colin A. Mckenzie, Aarno Palotie, Oluf Pedersen, Annette Peters, Konstantin Strauch, Bamidele O. Tayo, Nicholas J. Wareham, David A. Bennett, Lars Bertram, John Blangero, Matthias Blüher, Claude Bouchard, Harry Campbell, Nam H. Cho, Steven R. Cummings, Stefan A. Czerwinski, Ilja Demuth, Rahel Eckardt, Johan G. Eriksson, Luigi Ferrucci, Oscar H. Franco, Philippe Froguel, Ron T. Gansevoort, Torben Hansen, Tamara B. Harris, Nicholas Hastie, Markku Heliövaara, Albert Hofman, Joanne M. Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Paul B. Knekt, Seppo Koskinen, Peter Kovacs, Terho Lehtimäki, Lars Lind, Yongmei Liu, Eric S. Orwoll, Clive Osmond, Markus Perola, Louis Pérusse, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Treva K. Rice, Fernando Rivadeneira, Igor Rudan, Veikko Salomaa, Thorkild I. A. Sørensen, Michael Stumvoll, Anke Tönjes, Bradford Towne, Gregory J. Tranah, Angelo Tremblay, André G. Uitterlinden, Pim van der Harst, Erkki Vartiainen, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Henry Völzke, Mark Walker, Henri Wallaschofski, Sarah Wild, James F. Wilson, Loïc Yengo, D. Timothy Bishop, Ingrid B. Borecki, John C. Chambers, L. Adrienne Cupples, Abbas Dehghan, Panos Deloukas, Ghazaleh Fatemifar, Caroline Fox, Terrence S. Furey, Lude Franke, Jiali Han, David J. Hunter, Juha Karjalainen, Fredrik Karpe, Robert C. Kaplan, Jaspal S. Kooner, Mark I. McCarthy, Joanne M. Murabito, Andrew P. Morris, Julia A. N. Bishop, Kari E. North, Claes Ohlsson, Ken K. Ong, Inga Prokopenko, J. Brent Richards, Eric E. Schadt, Tim D. Spector, Elisabeth Widén, Cristen J. Willer, Jian Yang, Erik Ingelsson, Karen L. Mohlke, Joel N. Hirschhorn, John Andrew Pospisilik, M. Carola Zillikens, Cecilia Lindgren, Tuomas Oskari Kilpeläinen, and Ruth J. F. Loos

Subjects
Science
Abstract

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2016
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6. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith Foster, Qiong Yang, Ming-Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi-An Ko, Christian Fuchsberger, Bamidele Tayo, Michael Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Pio d’Adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. van der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, George B. Ehret, Georg Homuth, Stefan Coassin, Gian-Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H-Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, Ivana Persico, J. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean-Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo-Pekka Lyytikäinen, Loic Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia-Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst-Hensch, Nicole Soranzo, Olivier Devuyst, Olli Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L. R. Kardia, Sheila Ulivi, Shih-Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tonu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei-Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J. F. Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. de Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H. Linda Kao, and Caroline S. Fox

Subjects
Science
Abstract

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Published
2016
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7. Association of sex hormones with physical, laboratory, and imaging markers of anthropometry in men and women from the general population.

Author

Tom Seyfart, Nele Friedrich, Hanna Kische, Robin Bülow, Henri Wallaschofski, Henry Völzke, Matthias Nauck, Brian G Keevil, and Robin Haring

Subjects
Medicine, Science
Abstract

The aim of this study was to evaluate the association of sex hormones with anthropometry in a large population-based cohort, with liquid chromatography-mass spectrometry (LCMS)-based sex hormone measurements and imaging markers.Cross-sectional data from 957 men and women from the population-based Study of Health in Pomerania (SHIP) were used. Associations of a comprehensive panel of LCMS-measured sex hormones with anthropometric parameters, laboratory, and imaging markers were analyzed in multivariable regression models for the full sample and stratified by sex. Sex hormone measures included total testosterone (TT), free testosterone (fT), estrone and estradiol, androstenedione (ASD), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Domains of anthropometry included physical measures (body-mass-index (BMI), waist circumference, waist-to-height-ratio, waist-to-hip-ratio, and hip circumference), laboratory measures of adipokines (leptin and vaspin), and magnet resonance imaging-based measures (visceral and subcutaneous adipose tissue).In men, inverse associations between all considered anthropometric parameters with TT were found: BMI (β-coefficient, standard error (SE): -0.159, 0.037), waist-circumference (β-coefficient, SE: -0.892, 0.292), subcutaneous adipose tissue (β-coefficient, SE: -0.156, 0.023), and leptin (β-coefficient, SE: -0.046, 0.009). In women TT (β-coefficient, SE: 1.356, 0.615) and estrone (β-coefficient, SE: 0.014, 0.005) were positively associated with BMI. In analyses of variance, BMI and leptin were inversely associated with TT, ASD, and DHEAS in men, but positively associated with estrone. In women, BMI and leptin were positively associated with all sex hormones.The present population-based study confirmed and extended previously reported sex-specific associations between sex hormones and various anthropometric markers of overweight and obesity.

Published
2018
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8. Regional Variation of Chronic Kidney Disease in Germany: Results From Two Population-Based Surveys

Author

Nicole Aumann, Sebastian E. Baumeister, Rainer Rettig, Wolfgang Lieb, André Werner, Angela Döring, Annette Peters, Wolfgang Koenig, Anke Hannemann, Henri Wallaschofski, Matthias Nauck, Sylvia Stracke, Henry Völzke, and Christa Meisinger

Subjects
Albuminuria, Chronic kidney disease, Cohort study, Creatinine, Cystatin C, eGFR, Prevalence, Dermatology, RL1-803, Diseases of the circulatory (Cardiovascular) system, RC666-701, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Background/Aims: Due to the increasing prevalence of risk factors for chronic kidney disease (CKD), kidney dysfunction becomes a major public health problem. We investigated the CKD prevalence and determined to what extent the variation of risk factors explains the different CKD prevalence in Germany. Methods: We analyzed data from 6,054 participants, aged 31 to 82 years, from the Study of Health in Pomerania (SHIP-1) in Northeast Germany and the Cooperative Health Research in the Region of Augsburg (KORA F4) Study in Southern Germany. Regional differences in selected percentiles corresponding to the cutpoints for estimated glomerular filtration rate (eGFR, 2) and albumin-to-creatinine ratio (ACR, ≥30 mg/g) were tested using quantile regression models that adjusted for CKD risk factors. Results: The prevalence of decreased eGFRcreatinine-cystatinC (5.9 vs. 3.1 %, p creatinine-cystatinC and high ACR. Conclusions: The CKD prevalence is higher in Northeast than in Southern Germany. Differences in the prevalence of risk factors partly explain the higher disease burden of CKD in Northeast than in Southern Germany.

Published
2015
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9. Comprehensive metabolic characterization of serum osteocalcin action in a large non-diabetic sample.

Author

Lukas Entenmann, Maik Pietzner, Anna Artati, Anke Hannemann, Ann-Kristin Henning, Gabi Kastenmüller, Henry Völzke, Matthias Nauck, Jerzy Adamski, Henri Wallaschofski, and Nele Friedrich

Subjects
Medicine, Science
Abstract

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.

Published
2017
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10. Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis.

Author

Joel Eriksson, Robin Haring, Niels Grarup, Liesbeth Vandenput, Henri Wallaschofski, Erik Lorentzen, Torben Hansen, Dan Mellström, Oluf Pedersen, Matthias Nauck, Mattias Lorentzon, Lise Lotte Nystrup Husemoen, Henry Völzke, Magnus Karlsson, Sebastian E Baumeister, Allan Linneberg, and Claes Ohlsson

Subjects
Medicine, Science
Abstract

Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality.Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone.Bi-directional Mendelian randomization (MR) analysis on prospective cohorts.Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden).7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs.BMI and serum testosterone adjusted for age, smoking, time of blood sampling and site.1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42--0.09, p = 2.8*10-3). For a body weight reduction altering the BMI from 30 to 25 kg/m2, the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349).Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men.

Published
2017
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11. Urinary metabolomics reveals glycemic and coffee associated signatures of thyroid function in two population-based cohorts.

Author

Nele Friedrich, Maik Pietzner, Claire Cannet, Betina H Thuesen, Torben Hansen, Henri Wallaschofski, Niels Grarup, Tea Skaaby, Kathrin Budde, Oluf Pedersen, Matthias Nauck, and Allan Linneberg

Subjects
Medicine, Science
Abstract

Triiodothyronine (T3) and thyroxine (T4) as the main secretion products of the thyroid affect nearly every human tissue and are involved in a broad range of processes ranging from energy expenditure and lipid metabolism to glucose homeostasis. Metabolomics studies outside the focus of clinical manifest thyroid diseases are rare. The aim of the present investigation was to analyze the cross-sectional and longitudinal associations of urinary metabolites with serum free T4 (FT4) and thyroid-stimulating hormone (TSH).Urine Metabolites of participants of the population-based studies Inter99 (n = 5620) and Health2006/Health2008 (n = 3788) were analyzed by 1H-NMR spectroscopy. Linear or mixed linear models were used to detect associations between urine metabolites and thyroid function.Cross-sectional analyses revealed positive relations of alanine, trigonelline and lactic acid with FT4 and negative relations of dimethylamine, glucose, glycine and lactic acid with log(TSH). In longitudinal analyses, lower levels of alanine, dimethylamine, glycine, lactic acid and N,N-dimethylglycine were linked to a higher decline in FT4 levels over time, whereas higher trigonelline levels were related to a higher FT4 decline. Moreover, the risk of hypothyroidism was higher in subjects with high baseline trigonelline or low lactic acid, alanine or glycine values.The detected associations mainly emphasize the important role of thyroid hormones in glucose homeostasis. In addition, the predictive character of these metabolites might argue for a potential feedback of the metabolic state on thyroid function. Besides known metabolic consequences of TH, the link to the urine excretion of trigonelline, a marker of coffee consumption, represents a novel finding of this study and given the ubiquitous consumption of coffee requires further research.

Published
2017
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12. Associations of androgens with depressive symptoms and cognitive status in the general population.

Author

Hanna Kische, Stefan Gross, Henri Wallaschofski, Hans Jörgen Grabe, Henry Völzke, Matthias Nauck, and Robin Haring

Subjects
Medicine, Science
Abstract

OBJECTIVES:Associations between androgens and depressive symptoms were mostly reported from cross-sectional and patient-based studies. STUDY DESIGN/MAIN OUTCOME MEASURES:Longitudinal data from 4,110 participants of the Study of Health in Pomerania were used to assess sex-specific associations of baseline total and free testosterone, androstenedione and sex hormone-binding globulin with incident depressive symptoms and cognitive status at 5- and 10-year follow-up. RESULTS:Despite sex-specific differences in depressive symptoms prevalence at baseline (women: 17.4%, men: 8.1%), cross-sectional analyses showed no associations between sex hormones and depressive symptoms. In age-adjusted longitudinal analyses, total testosterone was associated with incident depressive symptoms (relative risk at 5-year follow-up: 0.73, 95% confidence interval: 0.58-0.92). Similarly, age-adjusted analyses showed a positive association between sex hormone-binding globulin and cognitive status in men (β-coefficient per standard deviation: 0.44, 95% confidence interval: 0.13-0.74). In women, age-adjusted associations of androstenedione with baseline depressive symptoms (relative risk: 0.88, 95% confidence interval: 0.77-0.99) were found. None of the observed associations remained after multivariable adjustment. CONCLUSIONS:The present population-based, longitudinal study revealed inverse associations between sex hormones and depressive symptoms. However, the null finding after multivariable adjustment suggests, that the observed associations were not independent of relevant confounders including body mass index, smoking and physical inactivity. Furthermore, the low number of incident endpoints in our non-clinical population-based sample limited the statistical power and reduced the chance to detect a statistically significant effect.

Published
2017
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13. Plasma Fibroblast Growth Factor 23: Clinical Correlates and Association With Cardiovascular Disease and Mortality in the Framingham Heart Study

Author

Robin Haring, Danielle Enserro, Vanessa Xanthakis, Gary F. Mitchell, Emelia J. Benjamin, Naomi M. Hamburg, Lisa Sullivan, Matthias Nauck, Henri Wallaschofski, and Ramachandran S. Vasan

Subjects
cardiovascular disease risk factors, epidemiology, metabolism, mineral, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundFibroblast 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 ResultsWe 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). ConclusionsIn our large, community‐based sample, FGF23 was associated with mortality risk, but not with vascular function or incident CVD.

Published
2016
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14. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos

Subjects
Genetics, QH426-470
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Published
2016
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15. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos

Subjects
Genetics, QH426-470
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

Published
2015
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16. Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality.

Author

Johannes Raffler, Nele Friedrich, Matthias Arnold, Tim Kacprowski, Rico Rueedi, Elisabeth Altmaier, Sven Bergmann, Kathrin Budde, Christian Gieger, Georg Homuth, Maik Pietzner, Werner Römisch-Margl, Konstantin Strauch, Henry Völzke, Melanie Waldenberger, Henri Wallaschofski, Matthias Nauck, Uwe Völker, Gabi Kastenmüller, and Karsten Suhre

Subjects
Genetics, QH426-470
Abstract

Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases.

Published
2015
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17. Associations between Serum Sex Hormone Concentrations and Whole Blood Gene Expression Profiles in the General Population.

Author

Robin Haring, Claudia Schurmann, Georg Homuth, Leif Steil, Uwe Völker, Henry Völzke, Brian G Keevil, Matthias Nauck, and Henri Wallaschofski

Subjects
Medicine, Science
Abstract

Despite observational evidence from epidemiological and clinical studies associating sex hormones with various cardiometabolic risk factors or diseases, pathophysiological explanations are sparse to date. To reveal putative functional insights, we analyzed associations between sex hormone levels and whole blood gene expression profiles.We used data of 991 individuals from the population-based Study of Health in Pomerania (SHIP-TREND) with whole blood gene expression levels determined by array-based transcriptional profiling and serum concentrations of total testosterone (TT), sex hormone-binding globulin (SHBG), free testosterone (free T), dehydroepiandrosterone sulfate (DHEAS), androstenedione (AD), estradiol (E2), and estrone (E1) measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassay. Associations between sex hormone concentrations and gene expression profiles were analyzed using sex-specific regression models adjusted for age, body mass index, and technical covariables.In men, positive correlations were detected between AD and DDIT4 mRNA levels, as well as between SHBG and the mRNA levels of RPIA, RIOK3, GYPB, BPGM, and RAB2B. No additional significant associations were observed.Besides the associations between AD and DDIT4 expression and SHBG and the transcript levels of RPIA, RIOK3, GYPB, BPGM, and RAB2B, the present study did not indicate any association between sex hormone concentrations and whole blood gene expression profiles in men and women from the general population.

Published
2015
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18. Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.

Author

Clive J Hoggart, Giulia Venturini, Massimo Mangino, Felicia Gomez, Giulia Ascari, Jing Hua Zhao, Alexander Teumer, Thomas W Winkler, Natalia Tšernikova, Jian'an Luan, Evelin Mihailov, Georg B Ehret, Weihua Zhang, David Lamparter, Tõnu Esko, Aurelien Macé, Sina Rüeger, Pierre-Yves Bochud, Matteo Barcella, Yves Dauvilliers, Beben Benyamin, David M Evans, Caroline Hayward, Mary F Lopez, Lude Franke, Alessia Russo, Iris M Heid, Erika Salvi, Sailaja Vendantam, Dan E Arking, Eric Boerwinkle, John C Chambers, Giovanni Fiorito, Harald Grallert, Simonetta Guarrera, Georg Homuth, Jennifer E Huffman, David Porteous, Generation Scotland Consortium, LifeLines Cohort study, GIANT Consortium, Darius Moradpour, Alex Iranzo, Johannes Hebebrand, John P Kemp, Gert J Lammers, Vincent Aubert, Markus H Heim, Nicholas G Martin, Grant W Montgomery, Rosa Peraita-Adrados, Joan Santamaria, Francesco Negro, Carsten O Schmidt, Robert A Scott, Tim D Spector, Konstantin Strauch, Henry Völzke, Nicholas J Wareham, Wei Yuan, Jordana T Bell, Aravinda Chakravarti, Jaspal S Kooner, Annette Peters, Giuseppe Matullo, Henri Wallaschofski, John B Whitfield, Fred Paccaud, Peter Vollenweider, Sven Bergmann, Jacques S Beckmann, Mehdi Tafti, Nicholas D Hastie, Daniele Cusi, Murielle Bochud, Timothy M Frayling, Andres Metspalu, Marjo-Riitta Jarvelin, André Scherag, George Davey Smith, Ingrid B Borecki, Valentin Rousson, Joel N Hirschhorn, Carlo Rivolta, Ruth J F Loos, and Zoltán Kutalik

Subjects
Genetics, QH426-470
Abstract

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P

Published
2014
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19. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Author

Marco Medici, Eleonora Porcu, Giorgio Pistis, Alexander Teumer, Suzanne J Brown, Richard A Jensen, Rajesh Rawal, Greet L Roef, Theo S Plantinga, Sita H Vermeulen, Jari Lahti, Matthew J Simmonds, Lise Lotte N Husemoen, Rachel M Freathy, Beverley M Shields, Diana Pietzner, Rebecca Nagy, Linda Broer, Layal Chaker, Tim I M Korevaar, Maria Grazia Plia, Cinzia Sala, Uwe Völker, J Brent Richards, Fred C Sweep, Christian Gieger, Tanguy Corre, Eero Kajantie, Betina Thuesen, Youri E Taes, W Edward Visser, Andrew T Hattersley, Jürgen Kratzsch, Alexander Hamilton, Wei Li, Georg Homuth, Monia Lobina, Stefano Mariotti, Nicole Soranzo, Massimiliano Cocca, Matthias Nauck, Christin Spielhagen, Alec Ross, Alice Arnold, Martijn van de Bunt, Sandya Liyanarachchi, Margit Heier, Hans Jörgen Grabe, Corrado Masciullo, Tessel E Galesloot, Ee M Lim, Eva Reischl, Peter J Leedman, Sandra Lai, Alessandro Delitala, Alexandra P Bremner, David I W Philips, John P Beilby, Antonella Mulas, Matteo Vocale, Goncalo Abecasis, Tom Forsen, Alan James, Elisabeth Widen, Jennie Hui, Holger Prokisch, Ernst E Rietzschel, Aarno Palotie, Peter Feddema, Stephen J Fletcher, Katharina Schramm, Jerome I Rotter, Alexander Kluttig, Dörte Radke, Michela Traglia, Gabriela L Surdulescu, Huiling He, Jayne A Franklyn, Daniel Tiller, Bijay Vaidya, Tim de Meyer, Torben Jørgensen, Johan G Eriksson, Peter C O'Leary, Eric Wichmann, Ad R Hermus, Bruce M Psaty, Till Ittermann, Albert Hofman, Emanuele Bosi, David Schlessinger, Henri Wallaschofski, Nicola Pirastu, Yurii S Aulchenko, Albert de la Chapelle, Romana T Netea-Maier, Stephen C L Gough, Henriette Meyer Zu Schwabedissen, Timothy M Frayling, Jean-Marc Kaufman, Allan Linneberg, Katri Räikkönen, Johannes W A Smit, Lambertus A Kiemeney, Fernando Rivadeneira, André G Uitterlinden, John P Walsh, Christa Meisinger, Martin den Heijer, Theo J Visser, Timothy D Spector, Scott G Wilson, Henry Völzke, Anne Cappola, Daniela Toniolo, Serena Sanna, Silvia Naitza, and Robin P Peeters

Subjects
Genetics, QH426-470
Abstract

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P

Published
2014
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20. No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.

Author

Jens Baumert, Jie Huang, Barbara McKnight, Maria Sabater-Lleal, Maristella Steri, Audrey Y Chu, Stella Trompet, Lorna M Lopez, Myriam Fornage, Alexander Teumer, Weihong Tang, Alicja R Rudnicka, Anders Mälarstig, Jouke-Jan Hottenga, Maryam Kavousi, Jari Lahti, Toshiko Tanaka, Caroline Hayward, Jennifer E Huffman, Pierre-Emmanuel Morange, Lynda M Rose, Saonli Basu, Ann Rumley, David J Stott, Brendan M Buckley, Anton J M de Craen, Serena Sanna, Marco Masala, Reiner Biffar, Georg Homuth, Angela Silveira, Bengt Sennblad, Anuj Goel, Hugh Watkins, Martina Müller-Nurasyid, Regina Rückerl, Kent Taylor, Ming-Huei Chen, Eco J C de Geus, Albert Hofman, Jacqueline C M Witteman, Moniek P M de Maat, Aarno Palotie, Gail Davies, David S Siscovick, Ivana Kolcic, Sarah H Wild, Jaejoon Song, Wendy L McArdle, Ian Ford, Naveed Sattar, David Schlessinger, Anne Grotevendt, Maria Grazia Franzosi, Thomas Illig, Melanie Waldenberger, Thomas Lumley, Geoffrey H Tofler, Gonneke Willemsen, André G Uitterlinden, Fernando Rivadeneira, Katri Räikkönen, Daniel I Chasman, Aaron R Folsom, Gordon D Lowe, Rudi G J Westendorp, P Eline Slagboom, Francesco Cucca, Henri Wallaschofski, Rona J Strawbridge, Udo Seedorf, Wolfgang Koenig, Joshua C Bis, Kenneth J Mukamal, Jenny van Dongen, Elisabeth Widen, Oscar H Franco, John M Starr, Kiang Liu, Luigi Ferrucci, Ozren Polasek, James F Wilson, Tiphaine Oudot-Mellakh, Harry Campbell, Pau Navarro, Stefania Bandinelli, Johan Eriksson, Dorret I Boomsma, Abbas Dehghan, Robert Clarke, Anders Hamsten, Eric Boerwinkle, J Wouter Jukema, Silvia Naitza, Paul M Ridker, Henry Völzke, Ian J Deary, Alexander P Reiner, David-Alexandre Trégouët, Christopher J O'Donnell, David P Strachan, Annette Peters, and Nicholas L Smith

Subjects
Medicine, Science
Abstract

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

Published
2014
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21. Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies.

Author

Judith S Brand, Maroeska M Rovers, Bu B Yeap, Harald J Schneider, Tomi-Pekka Tuomainen, Robin Haring, Giovanni Corona, Altan Onat, Marcello Maggio, Claude Bouchard, Peter C Y Tong, Richard Y T Chen, Masahiro Akishita, Jourik A Gietema, Marie-Hélène Gannagé-Yared, Anna-Lena Undén, Aarno Hautanen, Nicolai P Goncharov, Philip Kumanov, S A Paul Chubb, Osvaldo P Almeida, Hans-Ulrich Wittchen, Jens Klotsche, Henri Wallaschofski, Henry Völzke, Jussi Kauhanen, Jukka T Salonen, Luigi Ferrucci, and Yvonne T van der Schouw

Subjects
Medicine, Science
Abstract

BACKGROUND:Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. OBJECTIVES:We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. DATA SOURCES:Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. STUDY ELIGIBILITY CRITERIA:Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. METHODS:We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. RESULTS:Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. CONCLUSIONS:Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

Published
2014
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22. Incidence of all-cause and cardiovascular mortality predicted by symmetric dimethylarginine in the population-based study of health in pomerania.

Author

Edzard Schwedhelm, Henri Wallaschofski, Dorothee Atzler, Marcus Dörr, Matthias Nauck, Uwe Völker, Heyo K Kroemer, Henry Völzke, Rainer H Böger, and Nele Friedrich

Subjects
Medicine, Science
Abstract

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.

Published
2014
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23. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Author

Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Mace, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, SUNLIGHT Consortium, GEFOS Consortium, Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polasek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, and Murielle Bochud

Subjects
Genetics, QH426-470
Abstract

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

Published
2013
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24. Correlates of Adverse Outcomes in Abdominally Obese Individuals: Findings from the Five-Year Followup of the Population-Based Study of Health in Pomerania

Author

Nele Friedrich, Harald J. Schneider, Ulrich John, Marcus Dörr, Sebastian E. Baumeister, Georg Homuth, Uwe Völker, and Henri Wallaschofski

Subjects
Internal medicine, RC31-1245
Abstract

Background. Abdominal obesity is a major risk factor of cardiovascular disease (CVD), type 2 diabetes (T2DM), and premature death. However, it has not been resolved which factors predispose for the development of these adverse obesity-related outcomes in otherwise healthy individuals with abdominal obesity. Methods. We studied 1,506 abdominal obese individuals (waist-to-height ratio (WHtR) ≥ 0.5) free of CVD or T2DM from the population-based Study of Health in Pomerania and assessed the incidence of CVD or T2DM after a five-year followup. Logistic regression models were adjusted for major cardiovascular risk factors and liver, kidney diseases, and sociodemographic status. Results. During follow-up time, we observed 114 and 136 new T2DM and CVD cases, respectively. Regression models identified age, waist circumference, serum glucose, and liver disease as predictors of T2DM. Regarding CVD, only age, unemployment, and a divorced or widowed marital status were significantly associated with incident CVD. In this subgroup of obese individuals blood pressure, serum glucose, or lipids did not influence incidence of T2DM or CVD. Conclusion. We identified various factors associated with an increased risk of incident T2DM and CVD among abdominally obese individuals. These findings may improve the detection of high-risk individuals and help to advance prevention strategies in abdominal obesity.

Published
2013
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25. A network-based approach to visualize prevalence and progression of metabolic syndrome components.

Author

Robin Haring, Martin Rosvall, Uwe Völker, Henry Völzke, Heyo Kroemer, Matthias Nauck, and Henri Wallaschofski

Subjects
Medicine, Science
Abstract

BackgroundThe additional clinical value of clustering cardiovascular risk factors to define the metabolic syndrome (MetS) is still under debate. However, it is unclear which cardiovascular risk factors tend to cluster predominately and how individual risk factor states change over time.Methods and resultsWe used data from 3,187 individuals aged 20-79 years from the population-based Study of Health in Pomerania for a network-based approach to visualize clustered MetS risk factor states and their change over a five-year follow-up period. MetS was defined by harmonized Adult Treatment Panel III criteria, and each individual's risk factor burden was classified according to the five MetS components at baseline and follow-up. We used the map generator to depict 32 (2(5)) different states and highlight the most important transitions between the 1,024 (32(2)) possible states in the weighted directed network. At baseline, we found the largest fraction (19.3%) of all individuals free of any MetS risk factors and identified hypertension (15.4%) and central obesity (6.3%), as well as their combination (19.0%), as the most common MetS risk factors. Analyzing risk factor flow over the five-year follow-up, we found that most individuals remained in their risk factor state and that low high-density lipoprotein cholesterol (HDL) (6.3%) was the most prominent additional risk factor beyond hypertension and central obesity. Also among individuals without any MetS risk factor at baseline, low HDL (3.5%), hypertension (2.1%), and central obesity (1.6%) were the first risk factors to manifest during follow-up.ConclusionsWe identified hypertension and central obesity as the predominant MetS risk factor cluster and low HDL concentrations as the most prominent new onset risk factor.

Published
2012
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26. Analyzing illumina gene expression microarray data from different tissues: methodological aspects of data analysis in the metaxpress consortium.

Author

Claudia Schurmann, Katharina Heim, Arne Schillert, Stefan Blankenberg, Maren Carstensen, Marcus Dörr, Karlhans Endlich, Stephan B Felix, Christian Gieger, Harald Grallert, Christian Herder, Wolfgang Hoffmann, Georg Homuth, Thomas Illig, Jochen Kruppa, Thomas Meitinger, Christian Müller, Matthias Nauck, Annette Peters, Rainer Rettig, Michael Roden, Konstantin Strauch, Uwe Völker, Henry Völzke, Simone Wahl, Henri Wallaschofski, Philipp S Wild, Tanja Zeller, Alexander Teumer, Holger Prokisch, and Andreas Ziegler

Subjects
Medicine, Science
Abstract

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

Published
2012
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27. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.

Author

Andrea D Coviello, Robin Haring, Melissa Wellons, Dhananjay Vaidya, Terho Lehtimäki, Sarah Keildson, Kathryn L Lunetta, Chunyan He, Myriam Fornage, Vasiliki Lagou, Massimo Mangino, N Charlotte Onland-Moret, Brian Chen, Joel Eriksson, Melissa Garcia, Yong Mei Liu, Annemarie Koster, Kurt Lohman, Leo-Pekka Lyytikäinen, Ann-Kristin Petersen, Jennifer Prescott, Lisette Stolk, Liesbeth Vandenput, Andrew R Wood, Wei Vivian Zhuang, Aimo Ruokonen, Anna-Liisa Hartikainen, Anneli Pouta, Stefania Bandinelli, Reiner Biffar, Georg Brabant, David G Cox, Yuhui Chen, Steven Cummings, Luigi Ferrucci, Marc J Gunter, Susan E Hankinson, Hannu Martikainen, Albert Hofman, Georg Homuth, Thomas Illig, John-Olov Jansson, Andrew D Johnson, David Karasik, Magnus Karlsson, Johannes Kettunen, Douglas P Kiel, Peter Kraft, Jingmin Liu, Östen Ljunggren, Mattias Lorentzon, Marcello Maggio, Marcello R P Markus, Dan Mellström, Iva Miljkovic, Daniel Mirel, Sarah Nelson, Laure Morin Papunen, Petra H M Peeters, Inga Prokopenko, Leslie Raffel, Martin Reincke, Alex P Reiner, Kathryn Rexrode, Fernando Rivadeneira, Stephen M Schwartz, David Siscovick, Nicole Soranzo, Doris Stöckl, Shelley Tworoger, André G Uitterlinden, Carla H van Gils, Ramachandran S Vasan, H-Erich Wichmann, Guangju Zhai, Shalender Bhasin, Martin Bidlingmaier, Stephen J Chanock, Immaculata De Vivo, Tamara B Harris, David J Hunter, Mika Kähönen, Simin Liu, Pamela Ouyang, Tim D Spector, Yvonne T van der Schouw, Jorma Viikari, Henri Wallaschofski, Mark I McCarthy, Timothy M Frayling, Anna Murray, Steve Franks, Marjo-Riitta Järvelin, Frank H de Jong, Olli Raitakari, Alexander Teumer, Claes Ohlsson, Joanne M Murabito, and John R B Perry

Subjects
Genetics, QH426-470
Abstract

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Published
2012
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28. Incremental effects of endocrine and metabolic biomarkers and abdominal obesity on cardiovascular mortality prediction.

Author

Harald Jörn Schneider, Henri Wallaschofski, Henry Völzke, Marcello Ricardo Paulista Markus, Marcus Doerr, Stephan B Felix, Matthias Nauck, and Nele Friedrich

Subjects
Medicine, Science
Abstract

BACKGROUND: Biomarkers may help clinicians predict cardiovascular risk. We aimed to determine if the addition of endocrine, metabolic, and obesity-associated biomarkers to conventional risk factors improves the prediction of cardiovascular and all-cause mortality. METHODOLOGY/PRINCIPAL FINDINGS: In a population-based cohort study (the Study of Health in Pomerania) of 3,967 subjects (age 20-80 years) free of cardiovascular disease with a median follow-up of 10.0 years (38,638 person-years), we assessed the predictive value of conventional cardiovascular risk factors and the biomarkers thyrotropin; testosterone (in men only); insulin-like growth factor-1 (IGF-1); hemoglobin A1c (HbA1c); creatinine; high-sensitive C-reactive protein (hsCRP); fibrinogen; urinary albumin-to-creatinine ratio; and waist-to-height ratio (WHtR) on cardiovascular and all-cause death. During follow-up, we observed 339 all-cause including 103 cardiovascular deaths. In Cox regression models with conventional risk factors, the following biomarkers were retained as significant predictors of cardiovascular death after backward elimination: HbA1c, IGF-1, and hsCRP. IGF-1 and hsCRP were retained as significant predictors of all-cause death. For cardiovascular death, adding these biomarkers to the conventional risk factors changed the C-statistic from 0.898 to 0.910 (p = 0.02). The net reclassification improvement was 10.6%. For all-cause death, the C-statistic changed from 0.849 to 0.853 (P = 0.09). CONCLUSIONS/SIGNIFICANCE: HbA1c, IGF-1, and hsCRP predict cardiovascular death independently of conventional cardiovascular risk factors. These easily assessed endocrine and metabolic biomarkers might improve the ability to predict cardiovascular death.

Published
2012
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29. Genetic determinants of serum testosterone concentrations in men.

Author

Claes Ohlsson, Henri Wallaschofski, Kathryn L Lunetta, Lisette Stolk, John R B Perry, Annemarie Koster, Ann-Kristin Petersen, Joel Eriksson, Terho Lehtimäki, Ilpo T Huhtaniemi, Geoffrey L Hammond, Marcello Maggio, Andrea D Coviello, EMAS Study Group, Luigi Ferrucci, Margit Heier, Albert Hofman, Kate L Holliday, John-Olov Jansson, Mika Kähönen, David Karasik, Magnus K Karlsson, Douglas P Kiel, Yongmei Liu, Osten Ljunggren, Mattias Lorentzon, Leo-Pekka Lyytikäinen, Thomas Meitinger, Dan Mellström, David Melzer, Iva Miljkovic, Matthias Nauck, Maria Nilsson, Brenda Penninx, Stephen R Pye, Ramachandran S Vasan, Martin Reincke, Fernando Rivadeneira, Abdelouahid Tajar, Alexander Teumer, André G Uitterlinden, Jagadish Ulloor, Jorma Viikari, Uwe Völker, Henry Völzke, H Erich Wichmann, Tsung-Sheng Wu, Wei Vivian Zhuang, Elad Ziv, Frederick C W Wu, Olli Raitakari, Anna Eriksson, Martin Bidlingmaier, Tamara B Harris, Anna Murray, Frank H de Jong, Joanne M Murabito, Shalender Bhasin, Liesbeth Vandenput, and Robin Haring

Subjects
Genetics, QH426-470
Abstract

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as

Published
2011
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30. Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.

Author

Guangju Zhai, Alexander Teumer, Lisette Stolk, John R B Perry, Liesbeth Vandenput, Andrea D Coviello, Annemarie Koster, Jordana T Bell, Shalender Bhasin, Joel Eriksson, Anna Eriksson, Florian Ernst, Luigi Ferrucci, Timothy M Frayling, Daniel Glass, Elin Grundberg, Robin Haring, Asa K Hedman, Albert Hofman, Douglas P Kiel, Heyo K Kroemer, Yongmei Liu, Kathryn L Lunetta, Marcello Maggio, Mattias Lorentzon, Massimo Mangino, David Melzer, Iva Miljkovic, MuTHER Consortium, Alexandra Nica, Brenda W J H Penninx, Ramachandran S Vasan, Fernando Rivadeneira, Kerrin S Small, Nicole Soranzo, André G Uitterlinden, Henry Völzke, Scott G Wilson, Li Xi, Wei Vivian Zhuang, Tamara B Harris, Joanne M Murabito, Claes Ohlsson, Anna Murray, Frank H de Jong, Tim D Spector, and Henri Wallaschofski

Subjects
Genetics, QH426-470
Abstract

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.

Published
2011
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31. Screening for New Markers to Assess Thyroid Hormone Action by OMICs Analysis of Human Samples

Author

Nele Friedrich, Maik Pietzner, Georg Homuth, Uwe Völker, Georg Brabant, Henri Wallaschofski, Beatrice Engelmann, and Dagmar Führer

Subjects
0301 basic medicine, endocrine system, Proteome, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Population, Medizin, 030209 endocrinology & metabolism, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal Medicine, medicine, Central hypothyroidism, Humans, education, education.field_of_study, business.industry, Pituitary tumors, Thyroid, General Medicine, medicine.disease, Omics, Thyroid Diseases, Thyroid hormone resistance, 030104 developmental biology, medicine.anatomical_structure, Metabolome, Thyroid function, Transcriptome, business, Biomarkers, Hormone
Abstract

Determination of the levels of thyroid-stimulating hormone (TSH) and free thyroid hormones (fTHs) is crucial for assessing thyroid function. However, as a result of inter-individual genetic variability and different environmental factors individual set points exist for TSH and fTHs and display considerable variation. Furthermore, under specific pathophysiological conditions like central hypothyroidism, TSH secreting pituitary tumors, or thyroid hormone resistance the established markers TSH and fTH fail to reliably predict thyroid function and adequate supply of TH to peripheral organs. Even in case of overt hyper- and hypothyroidism circulating fTH concentrations do not correlate with clinical symptoms. Therefore, there is a clear need for novel, more specific biomarkers to diagnose and monitor thyroid function. OMICs screening approaches allow parallel profiling of hundreds to thousands of molecules and thus comprehensive monitoring of molecular alterations in tissues and body fluids that might be associated with changes in thyroid function. These techniques thus constitute promising tools for the identification of urgently needed novel biomarkers. This mini review summarizes the findings of OMICs studies in thyroid research with a particular focus on population-based and patient studies as well as interventional approaches investigating the effects of thyroid hormone administration.

Published
2020

32. Integrated biobanks facilitate high-quality collection and analysis of liquid biomaterials

Author

Henri Wallaschofski, Matthias Nauck, Christin Böttcher, Sophia Lamp, Christian Schäfer, Markus Roser, Astrid Petersmann, Steven Westphal, and Theresa Winter

Subjects
0301 basic medicine, Computer science, media_common.quotation_subject, Biochemistry (medical), Clinical Biochemistry, Biobank, Sample quality, 03 medical and health sciences, Engineering management, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Discrete Mathematics and Combinatorics, Quality (business), media_common
Abstract

The collection and storage of biomaterials is essential for medical research. The aim of biobanking is the safe extension of the preanalytical phase. However, not all quality aspects are clearly defined nor accepted by the whole biobanking community. Samples for large or complex trials have to be collected and stored according to well-defined, rapid and reliable processes. In a comparable manner, also the post-storage phase needs well-defined, rapid and reliable processes which have to be implemented in order to guarantee high-quality samples as an inevitable basis for accurate analytical results. The time span between the sample removal from the biobank and analysis seems not to be in the focus of a biobank especially when it is run independently of a laboratory. Sample analysis represents the core responsibility of laboratories. But the quality of samples can be impaired by all process steps in the preanalytical phase, including preparation for analysis after the freezing period. Biobanks may contribute to high-quality standards in the retrieval and handling of samples before storage. They can offer electronic tools for data entry in parallel to sampling allowing a tight control and documentation of the preanalytical phase directly in the laboratory information system. In case of a biobank independent of the laboratory, which performs the measurements, the biobank’s responsibility ends with the transport. A closer link between the two institutions, however, could significantly improve sample quality and laboratory results. Integrated biobanking combines long-term sample storage with optimized laboratory processes, thus facilitating high-quality analytical results.

Published
2019

33. Relation of IGF-I with subclinical cardiovascular markers including intima-media thickness, left ventricular mass index and NT-proBNP

Author

Henry Völzke, Stephan B. Felix, Ulf Schminke, Maximilian Eichner, Marcus Dörr, Matthias Nauck, Nele Friedrich, and Henri Wallaschofski

Subjects
Adult, Male, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Population, Carotid Intima-Media Thickness, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Cohort Studies, Endocrinology, Internal medicine, Linear regression, Natriuretic Peptide, Brain, Natriuretic peptide, Medicine, Humans, cardiovascular diseases, Insulin-Like Growth Factor I, education, Beta (finance), Subclinical infection, Aged, education.field_of_study, lcsh:RC648-665, business.industry, Confounding, General Medicine, Middle Aged, Peptide Fragments, Carotid Arteries, Insulin-Like Growth Factor Binding Protein 3, Intima-media thickness, Cardiovascular Diseases, Echocardiography, Cardiology, Female, business, hormones, hormone substitutes, and hormone antagonists, Cohort study
Abstract

Objective Several studies revealed relations between low or high insulin-like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms behind these associations are still unknown. Design The study aimed to explore the relations between IGF-I and changes in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ventricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Methods Longitudinal data of the population-based cohort Study of Health in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on echocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular confounders were performed. Results Statistical analyses demonstrated relations between low baseline IGF-I levels (beta for ΔIMT per s.d. increase −0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta −0.045 (0.012)) and a long-term IMT increase. No associations between IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline IGF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio with an increase in NT-proBNP were found. Conclusions The study detected significant relations between IGF-I and long-term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities.

Published
2019

34. Vitamin D and health care costs: Results from two independent population-based cohort studies

Author

Sebastian E. Baumeister, Paul Marschall, Steffen Flessa, Anke Hannemann, Henri Wallaschofski, Hans-Jörgen Grabe, M. Nauck, and C. O. Schmidt

Subjects
Adult, Male, Population, 030209 endocrinology & metabolism, Critical Care and Intensive Care Medicine, vitamin D deficiency, Cohort Studies, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Germany, Environmental health, Health care, Vitamin D and neurology, Humans, Medicine, 030212 general & internal medicine, Poisson regression, Vitamin D, education, Aged, education.field_of_study, Nutrition and Dietetics, business.industry, Health Care Costs, Middle Aged, Vitamin D Deficiency, medicine.disease, Hospitalization, Cross-Sectional Studies, Relative risk, Study of Health in Pomerania, symbols, Female, business, Cohort study
Abstract

Summary Background & aims Vitamin D deficiency is associated with higher morbidity. However, there is few data regarding the effect of vitamin D deficiency on health care costs. This study examined the cross-sectional and longitudinal associations between the serum 25-hydroxy vitamin D concentration (25OHD) and direct health care costs and hospitalization in two independent samples of the general population in North-Eastern Germany. Methods We studied 7217 healthy individuals from the ‘Study of Health in Pomerania’ (SHIP n = 3203) and the ‘Study of Health in Pomerania-Trend’ (SHIP-Trend n = 4014) who had valid 25OHD measurements and provided data on annual total costs, outpatient costs, hospital stays, and inpatient costs. The associations between 25OHD concentrations (modelled continuously using factional polynomials) and health care costs were examined using a generalized linear model with gamma distribution and a log link. Poisson regression models were used to estimate relative risks of hospitalization. Results In cross-sectional analysis of SHIP-Trend, non-linear associations between the 25OHD concentration and inpatient costs and hospitalization were detected: participants with 25OHD concentrations of 5, 10 and 15 ng/ml had 226.1%, 51.5% and 14.1%, respectively, higher inpatient costs than those with 25OHD concentrations of 20 ng/ml (overall p-value = 0.001) in multivariable models. Conclusions We found a relation between lower 25OHD concentrations and increased inpatient health care costs and hospitalization. Our results thus indicate an influence of vitamin D deficiency on health care costs in the general population.

Published
2018

35. Erkrankungen des äußeren Halses und der Halsweichteile

Author

Sören Wenzel, Gilfe Reiß, Olaf Michel, Henri Wallaschofski, Falk Thielemann, Gerd J. Ridder, Klaus-Peter Günther, and Michael Reiß

Abstract

Definition Alle bei der Entwicklung und Umbildung des Kiemendarms entstandenen Entwicklungsstorungen

Published
2021

36. Serum Glycine Levels Are Associated With Cortical Bone Properties and Fracture Risk in Men

Author

Mattias Lorentzon, Maria Nethander, Östen Ljunggren, Dan Mellström, Henri Wallaschofski, Anna Eriksson, Magnus Karlsson, Claes Ohlsson, and Nele Friedrich

Subjects
Male, medicine.medical_specialty, FRAX, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Population, Urology, Glycine, men, Context (language use), Orthopaedics, Endocrinology and Diabetes, Biochemistry, Risk Assessment, Endocrinology, Bone Density, BMD, Internal medicine, medicine, Cortical Bone, Humans, Prospective Studies, Quantitative computed tomography, education, Femoral neck, Aged, Bone mineral, Aged, 80 and over, Sweden, education.field_of_study, HR-pQCT, medicine.diagnostic_test, business.industry, Biochemistry (medical), Hazard ratio, Prognosis, medicine.anatomical_structure, Cross-Sectional Studies, fracture, Ortopedi, Endokrinologi och diabetes, Cortical bone, business, Biomarkers, Osteoporotic Fractures, Follow-Up Studies, glycine
Abstract

Context In a recent study a pattern of 27 metabolites, including serum glycine, associated with bone mineral density (BMD). Objective To investigate associations for serum and urinary glycine levels with BMD, bone microstructure, and fracture risk in men. Methods In the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (men, 69-81 years) serum glycine and BMD were measured at baseline (n = 965) and 5-year follow-up (n = 546). Cortical and trabecular bone parameters of the distal tibia were measured at follow-up using high-resolution peripheral quantitative computed tomography. Urinary (n = 2682) glycine was analyzed at baseline. X-ray-validated fractures (n = 594) were ascertained during a median follow-up of 9.6 years. Associations were evaluated using linear regression (bone parameters) or Cox regression (fractures). Results Circulating glycine levels were inversely associated with femoral neck (FN)-BMD. A meta-analysis (n = 7543) combining MrOS Sweden data with data from 3 other cohorts confirmed a robust inverse association between serum glycine levels and FN-BMD (P = 7.7 × 10-9). Serum glycine was inversely associated with the bone strength parameter failure load in the distal tibia (P = 0.002), mainly as a consequence of an inverse association with cortical cross-sectional area and a direct association with cortical porosity. Both serum and urinary glycine levels predicted major osteoporotic fractures (serum: hazard ratio [HR] per SD increase = 1.22, 95% CI, 1.05-1.43; urine: HR = 1.13, 95% CI, 1.02-1.24). These fracture associations were only marginally reduced in models adjusted by FRAX with BMD. Conclusions Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men.

Published
2021

37. Erkrankungen der Mundhöhle und der Lippen

Author

Henri Wallaschofski, Gerald Baier, Michael Reiß, Norbert H. Brockmeyer, Gilfe Reiß, Anja Potthoff, Josef G. Heckmann, Orlando Guntinas-Lichius, Thomas Hummel, Gerd J. Ridder, and Michael Herzog

Abstract

Angeborene kraniofaziale Dysplasie aufgrund von Entwicklungsanomalien der embryonalen Kopfanlage, der ersten beiden Viszeralbogen und der angrenzenden Furchen.

Published
2021

38. Evaluation of the metabotype concept identified in an irish population in the German KORA Cohort study

Author

Lorraine Brennan, Christa Meisinger, Martin Reincke, Christian Herder, Elaine Hillesheim, Michael Roden, Wolfgang Koenig, Jakob Linseisen, Henri Wallaschofski, Hans Hauner, Wolfgang Rathmann, Hannelore Daniel, Henry Völzke, Annette Peters, Florian Kronenberg, Nina Wawro, and Anna Riedl

Subjects
Ernährung, Adult, Blood Glucose, Male, 0301 basic medicine, Disease occurrence, Population, Biology, 03 medical and health sciences, Metabolic Diseases, Germany, Total cholesterol, Prevalence, Humans, Processed meat, ddc:610, education, Cardiometabolic Diseases, Diet, Enable Cluster, Metabolic Phenotypes, Metabotypes, Triglycerides, Aged, education.field_of_study, 030109 nutrition & dietetics, Cardiometabolic Risk Factors, Feeding Behavior, Middle Aged, DDC 600 / Technology (Applied sciences), Metabolic syndrome, ddc, enable cluster, metabotypes, Cardiovascular diseases, Cholesterol, 030104 developmental biology, Cardiovascular Diseases, Homogeneous, Risk stratification, Metabolome, Metabolic phenotype, Female, cardiometabolic diseases, ddc:600, Herzkrankheit, metabolic phenotypes, Metabolisches Syndrom, Food Science, Biotechnology, Demography, Cohort study
Abstract

Scope Previous work identified three metabolically homogeneous subgroups of individuals (“metabotypes”) using k-means cluster analysis based on fasting serum levels of triacylglycerol, total cholesterol, HDL cholesterol, and glucose. The aim is to reproduce these findings and describe metabotype groups by dietary habits and by incident disease occurrence. Methods and results 1744 participants from the KORA F4 study and 2221 participants from the KORA FF4 study are assigned to the three metabotype clusters previously identified by minimizing the Euclidean distances. In both KORA studies, the assignment of participants results in three metabolically distinct clusters, with cluster 3 representing the group of participants with the most unfavorable metabolic characteristics. Individuals of cluster 3 are further characterized by the highest incident disease occurrence during follow-up; they also reveal the most unfavorable diet with significantly lowest intakes of vegetables, dairy products, and fibers, and highest intakes of total, red, and processed meat. Conclusion The three metabotypes originally identified in an Irish population are successfully reproduced. In addition to this validation approach, the observed differences in disease incidence across metabotypes represent an important new finding that strongly supports the metabotyping approach as a tool for risk stratification., publishedVersion

Published
2020

39. HbA1c-Messung in Deutschland: Ist die Qualität ausreichend für Verlaufskontrolle und Diagnose?

Author

Rüdiger Landgraf, Guido Freckmann, Lutz Heinemann, Matthias Nauck, Wolfgang Kerner, J Roth, Henri Wallaschofski, Ludwig Merker, Denis Grote-Koska, Ulrich A. Müller, Patricia Kaiser, Michael Spannagl, and Dirk Müller-Wieland

Subjects
Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, Endocrinology, Diabetes and Metabolism, Political science, medicine, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology
Abstract

ZusammenfassungDie Bestimmung des HbA1c-Werts stellt eine wesentliche Labormessgröße zur Verlaufskontrolle und Therapieentscheidung bei Patienten mit Diabetes dar. Bereits aus der Verwendung des HbA1c-Werts für die Verlaufskontrolle sind hohe Anforderungen an die Messqualität der Messgröße ableitbar. Der Einsatz für die Diagnostik erfordert noch expliziter eine hohe analytische Richtigkeit und Präzision. Der HbA1c ist eine der Messgrößen in der Laboratoriumsmedizin, die nach den Richtlinien der Bundesärztekammer (Rili-BÄK) in der externen Qualitätskontrolle am Referenzmethodenwert bewertet werden können. Die seit vielen Jahren zulässige Abweichung von ± 18 % in Ringversuchen (RV) und von ± 10 % bei der internen Qualitätskontrolle konnte de facto von praktisch allen verschiedenen Anbietern und Methoden erfüllt werden. Allerdings führen diese weiten Grenzen für die zulässige Abweichung sowie der in der Vergangenheit übliche Einsatz von nicht für alle Systeme geeignetem Ringversuchsmaterial dazu, dass in der HbA1c-Analytik fehlerhafte Messwerte bzw. fehlkalibrierte Analysegeräte in Deutschland vom Anwender nur schwer identifiziert werden können. Mit der Einführung von unprozessiertem EDTA-Frischblut hat sich die Situation geändert. Dieses Ringversuchsmaterial kommt Patientenblut so nahe wie möglich. Artifizielle Matrixeffekte werden dadurch weitgehend vermieden. Im Sinne einer hohen Transparenz sollten auch in Deutschland die POCT-Systeme für die HbA1c-Messung an RV teilnehmen und alle Daten öffentlich gemacht werden. Es besteht zudem die Zielsetzung einer Angleichung der Maßgaben zu Qualitätskriterien an internationale Vorgaben. In diesem Positionspapier wird die Notwendigkeit einer Einengung der Akzeptanzgrenzen für die interne (auf ± 3 %) und externe (auf ± 8 %) Qualitätskontrolle von HbA1c in der Rili-BÄK dargelegt. Eine höhere Qualität bei den HbA1c-Messungen sollte dazu führen, dass bei weniger Patienten eine Fehldiagnose eines Diabetes erfolgt und möglicherweise falsche, zum Teil gefährliche Schlüsse für die Therapie erfolgen. Das technisch Machbare und Marktüberlegungen dürfen gegenüber medizinischen Anforderungen keine Rolle spielen. Angeregt wird eine Verbesserung der Kommunikation aller Beteiligten durch Etablierung eines „Round Table HbA1c“. Im gleichen Sinne sollte eine stärkere Einbindung der internationalen und europäischen Fachgesellschaften in den Bereichen Diabetologie (ADA/EASD) und Klinische Chemie (IFCC) in das Thema HbA1c-Messung erfolgen.

Published
2018

40. Abdominal fat deposits determined by magnetic resonance imaging in relation to leptin and vaspin levels as well as insulin resistance in the general adult population

Author

Nele Friedrich, J-P Kühn, Henry Völzke, F Genske, Maik Pietzner, Georg Homuth, Hans-Jörgen Grabe, Wlfgang Rathmann, and Henri Wallaschofski

Subjects
Adult, Leptin, Male, 0301 basic medicine, medicine.medical_specialty, Alcohol Drinking, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Population, Subcutaneous Fat, Medicine (miscellaneous), Adipokine, Adipose tissue, Enzyme-Linked Immunosorbent Assay, 030209 endocrinology & metabolism, Body Mass Index, Young Adult, 03 medical and health sciences, Age Distribution, 0302 clinical medicine, Insulin resistance, Germany, Internal medicine, medicine, Humans, Sex Distribution, education, Serpins, Aged, education.field_of_study, Nutrition and Dietetics, business.industry, Insulin, Smoking, Middle Aged, medicine.disease, Health Surveys, Magnetic Resonance Imaging, Obesity, 030104 developmental biology, Endocrinology, Liver, Study of Health in Pomerania, Female, Insulin Resistance, Sedentary Behavior, business, Biomarkers
Abstract

Various fat depots including visceral (VAT), subcutaneous adipose tissue (SAT) or liver fat content (LFC) were supposed to have different influences on various entities including adipokine levels as well as insulin resistance/sensitivity. Therefore, the aim of the study was to investigate the associations of SAT, VAT and LFC with the levels of leptin and vaspin as well as insulin resistance in a general non-diabetic population. In total, 1825 participants of the Study of Health in Pomerania were characterized according to body fat compartments and LFC determined by magnetic resonance imaging. Of those subjects, insulin resistance (HOMA-IR) and insulin sensitivity ([ISI(comp)) were determined in 981 participants and adipokines were assessed in 698 using enzyme-linked immunosorbent assay. Analyses of variance and linear regression models adjusted for age, sex, smoking, height, physical inactivity and alcohol consumption were used for analysis. Using the residual method to assess independently the effect of the various fat depots, a strong positive association of SAT (beta per standard deviation (s.d.) increase 0.54 (95% confidence interval (CI) 0.47–0.60)) but not VAT (beta 0.01 (95% CI −0.08 to 0.09)) and LFC (beta 0.01 (95% CI −0.06 to 0.08)) with log2-leptin levels was found independent of the HOMA-IR status. Moreover, a positive association of LFC (beta 0.17 (95% CI 0.07–0.26)) with log2-vaspin levels becomes apparent, which were mostly driven by subjects with a low HOMA-IR. With respect to HOMA-IR and ISI(comp) index, pronounced positive and inverse associations to all fat markers were revealed, respectively, with the strongest relation found for SAT and LFC. SAT and LFC were identified as predominant sites associated with leptin and vaspin levels, respectively. Residual analysis pointed towards a general adverse effect of disproportional triglyceride storage across physiological despots, in particular in ectopic sides such as the liver, with markers of insulin resistance.

Published
2017

41. Associations of aldosterone and renin concentrations with inflammation—the Study of Health in Pomerania and the German Conn’s Registry

Author

Martin Reincke, Wolfgang Hoffmann, Rainer Rettig, Anne Grotevendt, Marcus Quinkler, Christian Adolf, Henri Wallaschofski, Anke Hannemann, and M. Nauck

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Fibrinogen, Plasma renin activity, Cohort Studies, Leukocyte Count, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Primary aldosteronism, Reference Values, Germany, Internal medicine, Hyperaldosteronism, Renin, Renin–angiotensin system, medicine, Humans, Longitudinal Studies, Registries, education, Aldosterone, Inflammation, education.field_of_study, biology, business.industry, C-reactive protein, Middle Aged, medicine.disease, C-Reactive Protein, Socioeconomic Factors, chemistry, biology.protein, Female, business, Biomarkers, medicine.drug
Abstract

Chronic inflammation is an age-independent and body mass index-independent contributor to the development of multi-morbidity. Alterations of the renin-angiotensin-aldosterone system are observed within the context of proinflammatory states. We assessed circulating aldosterone, renin, and inflammatory biomarker concentrations in healthy, normotensive subjects and patients with primary aldosteronism. We included 1177 normotensive individuals from the population-based Study of Health in Pomerania (first follow-up, Study of Health in Pomerania-1) and 103 primary aldosteronism patients from the German Conn’s Registry. A 1:1 matching for sex, age, body mass index, smoking status, diabetes mellitus, and the estimated glomerular filtration rate was performed to determine whether primary aldosteronism patients exhibit higher inflammatory biomarker concentrations than normotensive controls. The associations of plasma aldosterone concentration or plasma renin concentration with circulating fibrinogen concentrations, white blood cell count, and high sensitive C-reactive protein concentrations in the normotensive sample were determined with multivariable linear and logistic regression analyses. 1:1 matched primary aldosteronism patients demonstrated significantly (p

Published
2017

42. Genetic Variants Associated with Circulating Parathyroid Hormone

Author

Mattias Lorentzon, Federico Murgia, Daniel L. Koller, Mario Pirastu, Matthias Nauk, Claes Ohlsson, Hoi Suen Wong, Weihong Tang, Joshua C. Bis, Jerome I. Rotter, Elizabeth A. Streeten, Carrie M. Nielson, Marcus E. Kleber, Bruce M. Psaty, Elizabeth Selvin, Lu-Chen Weng, Jack Pattee, Kathleen A. Ryan, Anke Hannemann, Georg Homuth, Michael J. Econs, Josef Coresh, Brenda W.J.H. Penninx, Uwe Völker, Alexander Teumer, David S. Siscovick, Henri Wallaschofski, Joel Eriksson, Braxton D. Mitchell, Pamela L. Lutsey, James S. Pankow, Bryan Kestenbaum, Frances M K Williams, Myles Wolf, Laura Portas, Andrew D. Paterson, Joseph M. Zmuda, Caroline S. Fox, Munro Peacock, Dongbing Lai, Stefan Pilz, Eric S. Orwoll, Maria Nethander, Cassianne Robinson-Cohen, Karen M. Eny, Yuri Milaneschi, José A. Riancho, W. März, Ian H. de Boer, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, APH - Mental Health, and APH - Digital Health

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Clinical Sciences, Parathyroid hormone, human genetics, Genome-wide association study, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, CYP24A1, Clinical Research, Internal medicine, medicine, Genetics, parathyroid hormone, SNP, Humans, 2.1 Biological and endogenous factors, Clinical Epidemiology, Polymorphism, Aetiology, Aged, genome-wide association study, Prevention, Human Genome, Genetic Variation, General Medicine, Single Nucleotide, Middle Aged, Urology & Nephrology, medicine.disease, mineral metabolism, Minor allele frequency, Europe, 030104 developmental biology, Endocrinology, Good Health and Well Being, Nephrology, Parathyroid Hormone, Secondary hyperparathyroidism, Female, Hormone
Abstract

© 2017 by the American Society of Nephrology. Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry.We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7%higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Published
2017

43. The Association between Bone Quality and Atherosclerosis: Results from Two Large Population-Based Studies

Author

V. Lange, Henry Völzke, Ulf Schminke, Matthias Nauck, Henri Wallaschofski, Anke Hannemann, and Marcus Dörr

Subjects
medicine.medical_specialty, Heel, Article Subject, Endocrinology, Diabetes and Metabolism, Population, Osteoporosis, 030209 endocrinology & metabolism, Logistic regression, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, cardiovascular diseases, 030212 general & internal medicine, education, education.field_of_study, lcsh:RC648-665, Endocrine and Autonomic Systems, business.industry, medicine.disease, medicine.anatomical_structure, Study of Health in Pomerania, cardiovascular system, Cardiology, Population study, Radiology, business, Dyslipidemia, Research Article, Cohort study
Abstract

Objective. It is highly debated whether associations between osteoporosis and atherosclerosis are independent of cardiovascular risk factors. We aimed to explore the associations between quantitative ultrasound (QUS) parameters at the heel with the carotid artery intima-media thickness (IMT), the presence of carotid artery plaques, and the ankle-brachial index (ABI). Methods. The study population comprised 5680 men and women aged 20–93 years from two population-based cohort studies: Study of Health in Pomerania (SHIP) and SHIP-Trend. QUS measurements were performed at the heel. The extracranial carotid arteries were examined with B-mode ultrasonography. ABI was measured in a subgroup of 3853 participants. Analyses of variance and linear and logistic regression models were calculated and adjusted for major cardiovascular risk factors. Results. Men but not women had significantly increased odds for carotid artery plaques with decreasing QUS parameters independent of diabetes mellitus, dyslipidemia, and hypertension. Beyond this, the QUS parameters were not significantly associated with IMT or ABI in fully adjusted models. Conclusions. Our data argue against an independent role of bone metabolism in atherosclerotic changes in women. Yet, in men, associations with advanced atherosclerosis, exist. Thus, men presenting with clinical signs of osteoporosis may be at increased risk for atherosclerotic disease.

Published
2017

44. Associations of plasma YKL-40 concentrations with heel ultrasound parameters and bone turnover markers in the general adult population

Author

Reiner Biffar, Maik Pietzner, Henri Wallaschofski, Uwe Völker, Stephan Michalik, Nele Friedrich, Matthias Nauck, Stefan Weiss, Anke Hannemann, Jörn Steinke, and Stefanie Samietz

Subjects
Adult, Male, musculoskeletal diseases, 0301 basic medicine, medicine.medical_specialty, Histology, Heel, Physiology, Endocrinology, Diabetes and Metabolism, Osteoporosis, Population, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Collagen Type I, Bone resorption, Bone remodeling, 03 medical and health sciences, 0302 clinical medicine, N-terminal telopeptide, Bone Density, Internal medicine, medicine, Humans, Chitinase-3-Like Protein 1, education, Ultrasonography, education.field_of_study, business.industry, medicine.disease, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Study of Health in Pomerania, Female, Bone Remodeling, business, Biomarkers, Procollagen
Abstract

Objective YKL-40, also known as chitinase-3-like protein 1, is a new proinflammatory biomarker, that might play a role in tissue remodeling and bone resorption. Here we evaluated the associations of the YKL-40 plasma concentration with heel ultrasound parameters and bone turnover markers (BTMs) in adult men and women from the general population. We tested for a causal role of YKL-40 on bone metabolism using published single nucleotide polymorphisms (SNPs) with consequences for YKL-40 expression and function. Methods Data were obtained from two population-based cohorts: the Study of Health in Pomerania (SHIP) and SHIP-Trend. Quantitative ultrasound (QUS) measurements at the heel were performed and bone turnover was assessed by measurement of intact amino-terminal propeptide of type I procollagen (PINP) and carboxy-terminal telopeptide of type I collagen (CTX). Associations between the YKL-40 plasma concentration and the QUS-based parameters, bone turnover marker (BTM) concentrations and 44 SNPs, including the lead SNP rs4950928, were evaluated in 382 subjects. Furthermore, we assessed the associations between the same SNPs and the QUS-based parameters (n = 5777) or the BTM concentrations (n = 7190). Results Sex-specific linear regression models adjusted for a comprehensive panel of interfering covariantes revealed statistically significant inverse associations between YKL-40 and all QUS-based parameters as well as positive associations with CTX in women. The rs4950928 polymorphism was associated with YKL-40 in men and women but none of the tested SNPs was associated with the QUS-based parameters or the BTMs after correction for multiple testing. Conclusions Plasma YKL-40 concentrations are associated with QUS-based parameters as well as CTX concentrations in women but these associations are probably not causal.

Published
2020

45. The Influence of Type 1 Diabetes Mellitus on Pulmonary Function and Exercise Capacity – Results from the Study of Health in Pomerania (SHIP)

Author

Sabine Schipf, Henri Wallaschofski, Ralf Ewert, Nele Friedrich, C Schäper, Sven Gläser, Henry Völzke, Matthias Nauck, Stephan B. Felix, Till Ittermann, Antje Steveling, and Beate Stubbe

Subjects
Adult, Male, medicine.medical_specialty, Vital capacity, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Pulmonary function testing, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Germany, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Lung volumes, education, Exercise, Aged, Aged, 80 and over, Type 1 diabetes, education.field_of_study, business.industry, Microangiopathy, General Medicine, Middle Aged, medicine.disease, Surgery, Diabetes Mellitus, Type 1, 030228 respiratory system, Study of Health in Pomerania, Physical Endurance, Cardiology, Female, Lung Volume Measurements, Pulmonary Ventilation, business
Abstract

Background: Diabetes mellitus Type 1 (T1DM) is associated with metabolic and microvascular diseases as part of a multi-organ and multi-systemic disorder. The dense network of capillary vessels in the lungs may change during the course of the development of microangiopathy. The connective tissue as well as alveoli may be subjected to non-enzymatic glycosylation of proteins which may in turn affect pulmonary function. Previous studies investigating lung function in patients with type 1 diabetes have only been performed on small numbers of patients. Our study is based on population data of the Study of Health in Pomerania (SHIP). Objective: To investigate the influence of metabolic control on pulmonary system function and to establish a decreased pulmonary system function as a late complication of T1DM in a population based setting. Methods: The study is a case matched study with multiple controls based on participants with T1DM (SHIP-DM-1, n=73) and non-diabetics (SHIP-1, n=292) from the population based study of Pomerania. Data on lung function and exercise performance stratified by age, sex, body mass index and smoking habits in participants with T1DM and without diabetes were matched. Results: Participants with T1DM showed a significantly lower total lung capacity, residual volume and forced vital capacity. The transfer factor for carbon monoxide, the maximum power output and oxygen uptake during exercise were significantly decreased in comparison to the general population without diabetes. Conclusion: The pattern of abnormal pulmonary function as observed in the present study with a reduction in lung volume parameters and reduced oxygen uptake in participants with T1DM suggests a restrictive type of lung disease caused by an intrinsic lung tissue derangement as well as pulmonary microangiopathy.

Published
2016

46. Reduced Bone Stiffness in Women Is Associated with Clinical Attachment and Tooth Loss

Author

Marcello Ricardo Paulista Markus, Marcus Dörr, D.M. Vargas, Peter Meisel, Thomas Kocher, Christiane Pink, Martin Albers, Henri Wallaschofski, Henry Völzke, Stefanie Samietz, João Luiz Gurgel Calvet da Silveira, Anke Hannemann, C. O. Schmidt, E.T. Santa Helena, Birte Holtfreter, and Caio Mauricio Mendes de Cordova

Subjects
Adult, Heel, genetic structures, Bone density, Osteoporosis, Population, Dentistry, 030209 endocrinology & metabolism, Tooth Loss, 03 medical and health sciences, Absorptiometry, Photon, 0302 clinical medicine, Bone Density, Risk Factors, Germany, Periodontal Attachment Loss, medicine, Tooth loss, Humans, education, General Dentistry, Aged, Aged, 80 and over, education.field_of_study, business.industry, 030206 dentistry, Middle Aged, medicine.disease, Confidence interval, Calcaneus, stomatognathic diseases, medicine.anatomical_structure, Clinical attachment loss, Study of Health in Pomerania, Female, medicine.symptom, business
Abstract

The authors evaluated the association of reduced bone stiffness of the calcaneus with clinical attachment loss (CAL) and tooth loss. The authors analyzed data from 4,678 subjects (2,384 women), aged 20 to 88 y, from the second follow-up of the population-based Study of Health in Pomerania (SHIP-2) and the baseline examination of the SHIP-Trend cohort. Bone stiffness, characterized by the stiffness index (SI) and the osteoporotic fracture risk (OFR), was assessed by quantitative ultrasound of the heel. SI and OFR were significantly associated with the mean CAL in women. While 1) the SI showed a significant association with the mean CAL and 2) the OFR with the median number of teeth in just the postmenopausal women, the OFR showed a significant association with mean CAL for both pre- and postmenopausal women. In postmenopausal women, a 10-unit increase in the SI was associated with a decrease in the mean CAL of 0.05 mm (95% confidence interval [CI]: –0.10 to 0.00; P = 0.046). Moreover, the adjusted median number of teeth was 21.4 (95% CI: 20.9 to 21.9) among the postmenopausal women with a low OFR, while it was 19.1 (95% CI: 17.8 to 20.3; P = 0.001) among the postmenopausal women with a high OFR. For the premenopausal women with a low OFR, the mean CAL was 1.60 mm (95% CI: 1.53 to 1.66), while for the premenopausal women with a high OFR, it was 2.24 mm (95% CI: 1.78 to 2.69; P = 0.006). Reduced bone stiffness was associated with clinical attachment and tooth loss in women but not in men.

Published
2016

47. Angiopoietin-2, its soluble receptor Tie-2, and metabolic syndrome components in a population-based sample

Author

Anne Grotevendt, Ramachandran S. Vasan, Marcus Dörr, Hans-Jörgen Grabe, Wolfgang Lieb, Sabrina Schlesinger, Henry Völzke, Henri Wallaschofski, Alexander Teumer, Sebastian E. Baumeister, Matthias Nauck, and Roberto Lorbeer

Subjects
0301 basic medicine, Percentile, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Medicine (miscellaneous), Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, education, Receptor, Subclinical infection, education.field_of_study, Nutrition and Dietetics, Cholesterol, business.industry, medicine.disease, 030104 developmental biology, chemistry, Study of Health in Pomerania, Metabolic syndrome, business
Abstract

Objective: Since angiopoietin-2 (Ang-2) levels strongly correlate with cardiovascular mortality and subclinical cardiovascular disease, it was hypothesized that levels of Ang-2 and its soluble receptor (sTie-2) were associated with the metabolic syndrome (MetS) and individual MetS components. Methods: Within the population-based Study of Health in Pomerania, two sets of analyses were performed. First, Ang-2 and sTie-2 were related to the prevalence of MetS and its components cross-sectionally (n=3,205). Second, the association between baseline Ang-2 and sTie-2 and incident MetS or longitudinal changes in its components in 1,295 individuals was investigated. Results: High Ang-2 levels (90th percentile), compared with low Ang-2 levels (10th percentile), were positively associated with MetS (OR: 1.78) and with the following MetS criteria: increased triglycerides, lower HDL cholesterol, and higher non-fasting glucose. Furthermore, high sTie-2 levels (90th percentile), compared with low levels (10th percentile), were positively related to MetS (OR: 1.58) and most of its components. However, Ang-2 and sTie-2 levels were not associated with incident MetS or longitudinal change in components of MetS. Conclusions: Ang-2 and sTie-2 levels were cross-sectionally associated with MetS and several of its components. However, Ang-2 and sTie-2 levels were not associated with incident MetS or changes in individual MetS components during follow-up.

Published
2016

48. Clinical correlates of sex hormones in women: The study of health in Pomerania

Author

Marcus Dörr, Stefan Gross, Henry Völzke, Robin Haring, Matthias Nauck, Henri Wallaschofski, and Hanna Kische

Subjects
Adult, medicine.medical_specialty, Waist, Health Status, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Estrone, 030204 cardiovascular system & hematology, Risk Assessment, Body Mass Index, Cohort Studies, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Sex hormone-binding globulin, Metabolic Diseases, Germany, Internal medicine, medicine, Humans, Gonadal Steroid Hormones, education, Testosterone, Aged, Aged, 80 and over, Metabolic Syndrome, Behavior, education.field_of_study, biology, Smoking, Middle Aged, medicine.disease, Cholesterol, Cross-Sectional Studies, Socioeconomic Factors, chemistry, Cardiovascular Diseases, Study of Health in Pomerania, Hypertension, biology.protein, Female, Waist Circumference, Metabolic syndrome, Body mass index
Abstract

Background Despite associations of sex hormones in women with increased cardiometabolic risk and mortality, the clinical correlates of altered sex hormone concentrations in women are less clearly understood. We investigated a broad range of clinical correlates of sex hormones in women from a large population-based sample. Methods Data from 2560 women from two cohorts of the Study of Health in Pomerania were used. Stepwise multivariable regression models were implemented to investigate a broad range of behavioral, socio-demographic, and cardiometabolic clinical correlates related to total testosterone (TT), free testosterone (fT), androstenedione (ASD), dehydroepiandrosterone-sulfate (DHEAS), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG). Results Waist circumference and BMI (β-coefficient: − 0.03; 95% CI: − 0.04; 0.03) were inversely related to SHBG, and BMI was positively related to TT (β-coefficient: 0.005; 95% CI: 0.001; 0.009), fT, E1, and E2. Smoking was positively related to TT (β-coefficient: 0.04; 95% CI: 0.01; 0.06), ASD, and fT. Systolic blood pressure (TT: β-coefficient: 0.002; 95% CI: 0.001; 0.003), hypertension (TT: β-coefficient: 0.05; 95% CI: 0.003; 0.11), low-density lipoprotein (LDL) cholesterol (TT: β-coefficient: 0.02; 95% CI: 0.01; 0.05), and total cholesterol (TT: β-coefficient: − 0.03; 95% CI: 0.01; 0.05) were positively related to TT and ASD. Finally, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS) were positively related to fT, but inversely related to SHBG. Conclusions Our population-based study, with sex hormone concentrations measured by liquid chromatography tandem mass spectrometry, revealed associations between clinical correlates including waist circumference, smoking, cohabitation, systolic blood pressure, cholesterol, and MetS with sex hormones. Thus, sex hormones and SHBG may play a role in the cardiovascular risk profile of women.

Published
2016

49. Associations of androgens with health care utilization and costs in women—Perspectives of a population-based cohort study

Author

Steffen Flessa, Henry Völzke, Brian G. Keevil, Robin Haring, Henri Wallaschofski, Matthias Nauck, and Sebastian E. Baumeister

Subjects
Adult, Gerontology, medicine.drug_class, Population, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Population based cohort, 0302 clinical medicine, Sex hormone-binding globulin, Germany, Sex Hormone-Binding Globulin, Health care, medicine, Humans, Testosterone, Prospective Studies, 030212 general & internal medicine, education, education.field_of_study, 030219 obstetrics & reproductive medicine, biology, business.industry, Obstetrics and Gynecology, Testosterone (patch), Health Care Costs, Middle Aged, Patient Acceptance of Health Care, Androgen, Confidence interval, Cross-Sectional Studies, Androgens, biology.protein, Female, business, Demography, Cohort study
Abstract

Objective Despite associations between total testosterone (TT) concentrations and increased cardiometabolic risk, the impact of serum androgens on health care utilization and costs among women is unknown. Methods We used data from 1521 women in the population-based cohort Study of Health in Pomerania (SHIP) to investigate the associations of serum TT (measured by liquid chromatography-tandem mass spectrometry), sex hormone-binding globulin (SHBG), and free testosterone (free T) with health care utilization and costs at baseline and five-year follow-up (N = 1210), implementing multivariable-adjusted econometric models. Results Cross-sectional analyses showed no association of TT, SHBG, or free T with hospitalization or total health costs (outpatient as well as inpatient costs). Prospective analyses revealed an inverse association of baseline SHBG with follow-up total health care costs (% change per standard deviation (SD): −26.2%, 95% confidence interval (CI): −42.2%; −8.9%) and inpatient costs (% change per SD: −26.5%%, 95% CI: −45.5%; −2.5%). Baseline free T was positively associated with total health care costs at the five-year follow-up (% change per SD: +37.7%, 95% CI: +4.6%; +81.4%). Conclusions In this first cost analysis among women from the general population, we observed no association of androgen serum concentration with health care utilization and costs. However, baseline SHBG appeared to be inversely correlated and free T positively correlated with long-term health care costs.

Published
2016

50. Prevalence of Malignancies in Patients With Primary Aldosteronism

Author

Holger S. Willenberg, Anke Hannemann, Stephanie Hahner, Martin Reincke, Marcus Quinkler, N Friedrichs, Lars Christian Rump, Ivo Quack, Anna Dietz, K Weber, Bruno Allolio, Carmina Teresa Fuss, Henri Wallaschofski, Katharina Lang, and Britta Heinze

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Population, Secondary hypertension, Blood Pressure, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Malignancy, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Primary aldosteronism, Renal cell carcinoma, Germany, Neoplasms, Internal medicine, Hyperaldosteronism, Biomarkers, Tumor, Prevalence, Humans, Medicine, Prospective Studies, education, Prospective cohort study, Aldosterone, Aged, Retrospective Studies, education.field_of_study, business.industry, Biochemistry (medical), Middle Aged, medicine.disease, chemistry, Case-Control Studies, Study of Health in Pomerania, Hypertension, Female, business
Abstract

Context: Primary aldosteronism (PA) is the most common cause of secondary hypertension. Aldosterone excess can cause DNA damage in vitro and in vivo. Single case reports have indicated a coincidence of PA with renal cell carcinoma and other tumors. However, the prevalence of benign and malignant neoplasms in patients with PA has not yet been studied. Patients and Design: In the multicenter MEPHISTO study, the prevalence of benign and malignant tumors was investigated in 335 patients with confirmed PA. Matched hypertensive subjects from the population-based Study of Health in Pomerania cohort served as controls. Results: Of the 335 PA patients, 119 (35.5%) had been diagnosed with a tumor at any time, and 30 had two or more neoplasms. Lifetime malignancy occurrence was reported in 9.6% of PA patients compared to 6.0% of hypertensive controls (P = .08). PA patients with a history of malignancy had higher baseline aldosterone levels at diagnosis of PA (P = .009), and a strong association between aldosterone levels and the prevalence of malignancies was observed (P = .03). In total, 157 neoplasms were identified in the PA patients; they were benign in 61% and malignant in 25% of the cases (14% of unknown dignity). Renal cell carcinoma was diagnosed in five patients (13% of all malignancies) and was not reported in controls. Conclusion: Compared to hypertensive controls, the prevalence of malignancies was positively correlated with aldosterone levels, tended to be higher in PA patients, but did not differ significantly.

Published
2016

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