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1. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author: Thomas W. Winkler, Humaira Rasheed, Alexander Teumer, Mathias Gorski, Bryce X. Rowan, Kira J. Stanzick, Laurent F. Thomas, Adrienne Tin, Anselm Hoppmann, Audrey Y. Chu, Bamidele Tayo, Chris H. L. Thio, Daniele Cusi, Jin-Fang Chai, Karsten B. Sieber, Katrin Horn, Man Li, Markus Scholz, Massimiliano Cocca, Matthias Wuttke, Peter J. van der Most, Qiong Yang, Sahar Ghasemi, Teresa Nutile, Yong Li, Giulia Pontali, Felix Günther, Abbas Dehghan, Adolfo Correa, Afshin Parsa, Agnese Feresin, Aiko P. J. de Vries, Alan B. Zonderman, Albert V. Smith, Albertine J. Oldehinkel, Alessandro De Grandi, Alexander R. Rosenkranz, Andre Franke, Andrej Teren, Andres Metspalu, Andrew A. Hicks, Andrew P. Morris, Anke Tönjes, Anna Morgan, Anna I. Podgornaia, Annette Peters, Antje Körner, Anubha Mahajan, Archie Campbell, Barry I. Freedman, Beatrice Spedicati, Belen Ponte, Ben Schöttker, Ben Brumpton, Bernhard Banas, Bernhard K. Krämer, Bettina Jung, Bjørn Olav Åsvold, Blair H. Smith, Boting Ning, Brenda W. J. H. Penninx, Brett R. Vanderwerff, Bruce M. Psaty, Candace M. Kammerer, Carl D. Langefeld, Caroline Hayward, Cassandra N. Spracklen, Cassianne Robinson-Cohen, Catharina A. Hartman, Cecilia M. Lindgren, Chaolong Wang, Charumathi Sabanayagam, Chew-Kiat Heng, Chiara Lanzani, Chiea-Chuen Khor, Ching-Yu Cheng, Christian Fuchsberger, Christian Gieger, Christian M. Shaffer, Christina-Alexandra Schulz, Cristen J. Willer, Daniel I. Chasman, Daniel F. Gudbjartsson, Daniela Ruggiero, Daniela Toniolo, Darina Czamara, David J. Porteous, Dawn M. Waterworth, Deborah Mascalzoni, Dennis O. Mook-Kanamori, Dermot F. Reilly, E. Warwick Daw, Edith Hofer, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, E-Shyong Tai, Eulalia Catamo, Federica Rizzi, Feng Guo, Fernando Rivadeneira, Franco Guilianini, Gardar Sveinbjornsson, Georg Ehret, Gerard Waeber, Ginevra Biino, Giorgia Girotto, Giorgio Pistis, Girish N. Nadkarni, Graciela E. Delgado, Grant W. Montgomery, Harold Snieder, Harry Campbell, Harvey D. White, He Gao, Heather M. Stringham, Helena Schmidt, Hengtong Li, Hermann Brenner, Hilma Holm, Holgen Kirsten, Holly Kramer, Igor Rudan, Ilja M. Nolte, Ioanna Tzoulaki, Isleifur Olafsson, Jade Martins, James P. Cook, James F. Wilson, Jan Halbritter, Janine F. Felix, Jasmin Divers, Jaspal S. Kooner, Jeannette Jen-Mai Lee, Jeffrey O’Connell, Jerome I. Rotter, Jianjun Liu, Jie Xu, Joachim Thiery, Johan Ärnlöv, Johanna Kuusisto, Johanna Jakobsdottir, Johanne Tremblay, John C. Chambers, John B. Whitfield, John M. Gaziano, Jonathan Marten, Josef Coresh, Jost B. Jonas, Josyf C. Mychaleckyj, Kaare Christensen, Kai-Uwe Eckardt, Karen L. Mohlke, Karlhans Endlich, Katalin Dittrich, Kathleen A. Ryan, Kenneth M. Rice, Kent D. Taylor, Kevin Ho, Kjell Nikus, Koichi Matsuda, Konstantin Strauch, Kozeta Miliku, Kristian Hveem, Lars Lind, Lars Wallentin, Laura M. Yerges-Armstrong, Laura M. Raffield, Lawrence S. Phillips, Lenore J. Launer, Leo-Pekka Lyytikäinen, Leslie A. Lange, Lorena Citterio, Lucija Klaric, M. Arfan Ikram, Marcus Ising, Marcus E. Kleber, Margherita Francescatto, Maria Pina Concas, Marina Ciullo, Mario Piratsu, Marju Orho-Melander, Markku Laakso, Markus Loeffler, Markus Perola, Martin H. de Borst, Martin Gögele, Martina La Bianca, Mary Ann Lukas, Mary F. Feitosa, Mary L. Biggs, Mary K. Wojczynski, Maryam Kavousi, Masahiro Kanai, Masato Akiyama, Masayuki Yasuda, Matthias Nauck, Melanie Waldenberger, Miao-Li Chee, Miao-Ling Chee, Michael Boehnke, Michael H. Preuss, Michael Stumvoll, Michael A. Province, Michele K. Evans, Michelle L. O’Donoghue, Michiaki Kubo, Mika Kähönen, Mika Kastarinen, Mike A. Nalls, Mikko Kuokkanen, Mohsen Ghanbari, Murielle Bochud, Navya Shilpa Josyula, Nicholas G. Martin, Nicholas Y. Q. Tan, Nicholette D. Palmer, Nicola Pirastu, Nicole Schupf, Niek Verweij, Nina Hutri-Kähönen, Nina Mononen, Nisha Bansal, Olivier Devuyst, Olle Melander, Olli T. Raitakari, Ozren Polasek, Paolo Manunta, Paolo Gasparini, Pashupati P. Mishra, Patrick Sulem, Patrik K. E. Magnusson, Paul Elliott, Paul M. Ridker, Pavel Hamet, Per O. Svensson, Peter K. Joshi, Peter Kovacs, Peter P. Pramstaller, Peter Rossing, Peter Vollenweider, Pim van der Harst, Rajkumar Dorajoo, Ralene Z. H. Sim, Ralph Burkhardt, Ran Tao, Raymond Noordam, Reedik Mägi, Reinhold Schmidt, Renée de Mutsert, Rico Rueedi, Rob M. van Dam, Robert J. Carroll, Ron T. Gansevoort, Ruth J. F. Loos, Sala Cinzia Felicita, Sanaz Sedaghat, Sandosh Padmanabhan, Sandra Freitag-Wolf, Sarah A. Pendergrass, Sarah E. Graham, Scott D. Gordon, Shih-Jen Hwang, Shona M. Kerr, Simona Vaccargiu, Snehal B. Patil, Stein Hallan, Stephan J. L. Bakker, Su-Chi Lim, Susanne Lucae, Suzanne Vogelezang, Sven Bergmann, Tanguy Corre, Tarunveer S. Ahluwalia, Terho Lehtimäki, Thibaud S. Boutin, Thomas Meitinger, Tien-Yin Wong, Tobias Bergler, Ton J. Rabelink, Tõnu Esko, Toomas Haller, Unnur Thorsteinsdottir, Uwe Völker, Valencia Hui Xian Foo, Veikko Salomaa, Veronique Vitart, Vilmantas Giedraitis, Vilmundur Gudnason, Vincent W. V. Jaddoe, Wei Huang, Weihua Zhang, Wen Bin Wei, Wieland Kiess, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Xin Gao, Xueling Sim, Ya Xing Wang, Yechiel Friedlander, Yih-Chung Tham, Yoichiro Kamatani, Yukinori Okada, Yuri Milaneschi, Zhi Yu, Lifelines cohort study, DiscovEHR/MyCode study, VA Million Veteran Program, Klaus J. Stark, Kari Stefansson, Carsten A. Böger, Adriana M. Hung, Florian Kronenberg, Anna Köttgen, Cristian Pattaro, and Iris M. Heid
Subjects: Biology (General), QH301-705.5
Abstract: A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.
Published: 2022
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2. The cytokines HGF and CXCL13 predict the severity and the mortality in COVID-19 patients

Author: Matthieu Perreau, Madeleine Suffiotti, Pedro Marques-Vidal, Aurelie Wiedemann, Yves Levy, Cédric Laouénan, Jade Ghosn, Craig Fenwick, Denis Comte, Thierry Roger, Jean Regina, Peter Vollenweider, Gerard Waeber, Mauro Oddo, Thierry Calandra, and Giuseppe Pantaleo
Subjects: Science
Abstract: Infection with SARS CoV2 results in the induction of multiple cytokine and inflammatory pathways. Here the authors demonstrate the association of HGF and CXCL13 production with increased severity and mortality in COVID-19 patients.
Published: 2021
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3. Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes

Author: Eleonora Porcu, Federica Gilardi, Liza Darrous, Loic Yengo, Nasim Bararpour, Marie Gasser, Pedro Marques-Vidal, Philippe Froguel, Gerard Waeber, Aurelien Thomas, and Zoltán Kutalik
Subjects: Medicine, Science
Abstract: Abstract The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
Published: 2021
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4. Clinical and biological determinants of P-wave duration: cross-sectional data from the population-based CoLaus|PsyCoLaus study

Author: Pedro Marques-Vidal, Peter Vollenweider, Federica Bocchi, Etienne Pruvot, Gerard Waeber, and David Gachoud
Subjects: Medicine
Abstract: Objectives P-wave duration (PWD) is associated with the development of atrial arrhythmias, cardiovascular and all-cause mortality. With this study, we aimed to assess the distribution and determinants of PWD in the general population.Design Cross-sectional study using data collected between 2014 and 2016.Setting In the population-based cohort CoLaus|PsyCoLaus, Lausanne, Switzerland, we used 12-lead ECGs to measure PWD. Potential demographic, clinical and biological determinants of PWD were collected by questionnaire, anthropometry, blood pressure measurement and biological assays.Participants Data from 3459 participants (55% women, 62±10 years, 93% Caucasian) were included. Participants were excluded if they presented with (1) no sinus rhythm or paced rhythm on the study ECG or Wolff-Parkinson-White ECG pattern; (2) missing or non-interpretable ECG; and (3) missing phenotypic data.Primary outcome measure Determine (1) the PWD distribution and (2) the demographic, clinical and biological determinants of PWD in a large population-based cohort.Results Median and IQR of PWD was 112 (102–120) ms . In the multivariable analyses, PWD was significantly associated with age (p
Published: 2020
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5. Prognostic and therapeutic considerations of antibodies against c‐ter apolipoprotein A‐1 in the general population

Author: Nicolas Vuilleumier, Panagiotis Antiochos, Pedro Marques‐Vidal, Sabrina Pagano, Julien Virzi, Nathalie Satta, Oliver Hartley, Hubert Gaertner, Karim J Brandt, Fabienne Burger, Fabrizio Montecucco, Gerard Waeber, François Mach, and Peter Vollenweider
Subjects: anti‐apoA‐1 IgG, ApoE−/− mice, CoLaus study, C‐terminal A1 peptide, passive immunisation, Immunologic diseases. Allergy, RC581-607
Abstract: Abstract Objectives Autoantibodies against apolipoprotein A1 (anti‐apoA1 IgGs) and its C‐terminal region (cter apoA1) have emerged as an independent biomarker for cardiovascular disease. Cter apoA1 mimetic peptides were shown to reverse the deleterious anti‐apoA1 IgG effects in vitro. We evaluated the association of anti‐cter apoA1 IgGs with overall mortality in the general population and tested the ability of a cter apoA1 mimetic peptide to reverse the anti‐apoA1 IgG‐induced inflammatory response and mortality in vitro and in vivo, respectively. Methods Anti‐cter apoA1 IgGs were measured in serum samples of 6386 participants of the CoLaus study of which 5220 were followed for a median duration of 5.6 years. The primary outcome was overall mortality. The peptide inhibitory concentration 50% (IC50) was determined in vitro on HEK‐Blue‐4 and RAW cells. ApoE−/− mice were exposed to 16 weeks of anti‐apoA1IgG passive immunisation with and without peptide co‐incubation. Results Anti‐cter apoA1 IgGs were associated with higher interleukin 6 levels and independently predicted overall mortality; an increase of one standard deviation of anti‐cter apoA1 IgG level was associated with an 18% increase in mortality risk (hazard ratio: 1.18, 95% confidence interval: 1.04–1.33; P = 0.009). The cterApoA1 analogue reversed the antibody‐mediated inflammatory response with an IC50 of 1 µm in vitro but did not rescue the significant anti‐apoA1 IgG‐induced mortality rate in vivo (69% vs. 23%, LogRank P = 0.02). Conclusion Anti‐cter apoA1 IgG independently predicts overall mortality in the general population. Despite being effective in vitro, our cter apoA1 analogue did not reverse the anti‐apoA1 IgG‐induced mortality in mice. Our data suggest that these autoantibodies are not readily treatable through cognate peptide immunomodulation.
Published: 2020
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6. Use of oscillometric devices in atrial fibrillation: a comparison of three devices and invasive blood pressure measurement

Author: Matthieu Halfon, Gregoire Wuerzner, Pedro Marques-Vidal, Patrick Taffe, Julien Vaucher, Bernard Waeber, Lucas Liaudet, Zied Ltaief, Milen Popov, and Gerard Waeber
Subjects: blood pressure, atrial fibrillation, oscillometric device, hypertension, limits of agreement, invasive blood pressure, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background: The use of automated (oscillometric) blood pressure (BP) devices is not validated in atrial fibrillation (AF) patients. Objectives: To assess the reliability of three oscillometric BP devices, and the agreement with invasive arterial blood pressure(IBP) in AF patients. Methods: 48 AF patients with randomized sequences of 10 consecutive BP measurements with two pairs of devices: (1) OmronR7™(wrist) and OmronHEM907™(arm); (2) OmronR7™ and Microlife WatchBPhome(arm). Reliability and agreement of each device were assessed by the intra-class correlation coefficient (ICC) for the continuous BP measurements and Bland & Altman methodology, respectively. In 10 additional AF patients, 10 consecutive measurements with IBP and OmronHEM907™, and IBP and Microlife WatchBPhome were performed. Results: The OmronR7™ was not able to obtain any BP Readings. Arm devices presented better ICC for systolicBP(SBP) than for diastolicBP(DBP) (Omron HEM907™:0.94 [0.90; 0.97] vs. 0.77 [0.67; 0.89]; Microlife WatchBPhome:0.92 [0.88; 0.96] vs.0.79 [0.69; 0.89]).The correlation coefficient between Microlife WatchBPhome and IBP computed using the average of repeated measurements from two to ten measurements improved up to the third and remained stable afterwards. The agreement between IBP and SBP, and IBP and DBP, was moderate as illustrated by a wide limit of agreement [−24; 26](SBP) and [−15;17](DBP) for Microlife WatchBPHome, respectively and [−30; 13](SBP) and [−7; 15](DBP) for OmronHEM907. Conclusions: BP measurement using the two arm oscillometric devices achieved a high reliability for SBP. The agreement between IBP and arm devices was low but using the average of three consecutive measurements improved the results substantially.
Published: 2018
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7. A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms[S]

Author: Salome Mack, Stefan Coassin, Rico Rueedi, Noha A. Yousri, Ilkka Seppälä, Christian Gieger, Sebastian Schönherr, Lukas Forer, Gertraud Erhart, Pedro Marques-Vidal, Janina S. Ried, Gerard Waeber, Sven Bergmann, Doreen Dähnhardt, Andrea Stöckl, Olli T. Raitakari, Mika Kähönen, Annette Peters, Thomas Meitinger, Konstantin Strauch, Ludmilla Kedenko, Bernhard Paulweber, Terho Lehtimäki, Steven C. Hunt, Peter Vollenweider, Claudia Lamina, and Florian Kronenberg
Subjects: genetics, epidemiology, coronary artery disease, Biochemistry, QD415-436
Abstract: High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10−30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10−10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the populationŉs mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10−4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.
Published: 2017
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8. The Metabolic Benefits of Menopausal Hormone Therapy Are Not Mediated by Improved Nutritional Habits. The OsteoLaus Cohort

Author: Georgios E. Papadakis, Didier Hans, Elena Gonzalez Rodriguez, Peter Vollenweider, Gerard Waeber, Pedro Marques-Vidal, and Olivier Lamy
Subjects: menopause, estrogens, estrogen deficiency, visceral fat, menopausal hormone therapy, energy intake, macronutrients, dietary patterns, dietary recommendations, Nutrition. Foods and food supply, TX341-641
Abstract: Menopause alters body composition by increasing fat mass. Menopausal hormone therapy (MHT) is associated with decreased total and visceral adiposity. It is unclear whether MHT favorably affects energy intake. We aimed to assess in the OsteoLaus cohort whether total energy intake (TEI) and/or diet quality (macro- and micronutrients, dietary patterns, dietary scores, dietary recommendations)—evaluated by a validated food frequency questionnaire—differ in 839 postmenopausal women classified as current, past or never MHT users. There was no difference between groups regarding TEI or consumption of macronutrients. After multivariable adjustment, MHT users were less likely to adhere to the unhealthy pattern ‘fat and sugar: Current vs. never users [OR (95% CI): 0.48 (0.28−0.82)]; past vs. never users [OR (95% CI): 0.47 (0.27−0.78)]. Past users exhibited a better performance in the revised score for Mediterranean diet than never users (5.00 ± 0.12 vs. 4.63 ± 0.08, p < 0.04). Differences regarding compliance with dietary recommendations were no longer significant after adjustment for covariates. Overall, these results argue against a major role of TEI and diet quality as possible mediators of the MHT metabolic benefits. Future research on this relationship should focus on other potential targets of MHT, such as resting energy expenditure and physical activity.
Published: 2019
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9. Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans.

Author: Stela McLachlan, Claudia Giambartolomei, Jon White, Pimphen Charoen, Andrew Wong, Chris Finan, Jorgen Engmann, Tina Shah, Micha Hersch, Clara Podmore, Alana Cavadino, Barbara J Jefferis, Caroline E Dale, Elina Hypponen, Richard W Morris, Juan P Casas, Meena Kumari, Yoav Ben-Shlomo, Tom R Gaunt, Fotios Drenos, Claudia Langenberg, Diana Kuh, Mika Kivimaki, Rico Rueedi, Gerard Waeber, Aroon D Hingorani, Jacqueline F Price, Ann P Walker, and UCLEB Consortium
Subjects: Medicine, Science
Abstract: Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.
Published: 2016
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10. Modulation of genetic associations with serum urate levels by body-mass-index in humans.

Author: Jennifer E Huffman, Eva Albrecht, Alexander Teumer, Massimo Mangino, Karen Kapur, Toby Johnson, Zoltán Kutalik, Nicola Pirastu, Giorgio Pistis, Lorna M Lopez, Toomas Haller, Perttu Salo, Anuj Goel, Man Li, Toshiko Tanaka, Abbas Dehghan, Daniela Ruggiero, Giovanni Malerba, Albert V Smith, Ilja M Nolte, Laura Portas, Amanda Phipps-Green, Lora Boteva, Pau Navarro, Asa Johansson, Andrew A Hicks, Ozren Polasek, Tõnu Esko, John F Peden, Sarah E Harris, Federico Murgia, Sarah H Wild, Albert Tenesa, Adrienne Tin, Evelin Mihailov, Anne Grotevendt, Gauti K Gislason, Josef Coresh, Pio D'Adamo, Sheila Ulivi, Peter Vollenweider, Gerard Waeber, Susan Campbell, Ivana Kolcic, Krista Fisher, Margus Viigimaa, Jeffrey E Metter, Corrado Masciullo, Elisabetta Trabetti, Cristina Bombieri, Rossella Sorice, Angela Döring, Eva Reischl, Konstantin Strauch, Albert Hofman, Andre G Uitterlinden, Melanie Waldenberger, H-Erich Wichmann, Gail Davies, Alan J Gow, Nicola Dalbeth, Lisa Stamp, Johannes H Smit, Mirna Kirin, Ramaiah Nagaraja, Matthias Nauck, Claudia Schurmann, Kathrin Budde, Susan M Farrington, Evropi Theodoratou, Antti Jula, Veikko Salomaa, Cinzia Sala, Christian Hengstenberg, Michel Burnier, Reedik Mägi, Norman Klopp, Stefan Kloiber, Sabine Schipf, Samuli Ripatti, Stefano Cabras, Nicole Soranzo, Georg Homuth, Teresa Nutile, Patricia B Munroe, Nicholas Hastie, Harry Campbell, Igor Rudan, Claudia Cabrera, Chris Haley, Oscar H Franco, Tony R Merriman, Vilmundur Gudnason, Mario Pirastu, Brenda W Penninx, Harold Snieder, Andres Metspalu, Marina Ciullo, Peter P Pramstaller, Cornelia M van Duijn, Luigi Ferrucci, Giovanni Gambaro, Ian J Deary, Malcolm G Dunlop, James F Wilson, Paolo Gasparini, Ulf Gyllensten, Tim D Spector, Alan F Wright, Caroline Hayward, Hugh Watkins, Markus Perola, Murielle Bochud, W H Linda Kao, Mark Caulfield, Daniela Toniolo, Henry Völzke, Christian Gieger, Anna Köttgen, and Veronique Vitart
Subjects: Medicine, Science
Abstract: We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
Published: 2015
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11. Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression.

Author: Aurélie Delacrétaz, Martin Preisig, Frederik Vandenberghe, Nuria Saigi Morgui, Lina Quteineh, Eva Choong, Mehdi Gholam-Rezaee, Zoltan Kutalik, Pierre Magistretti, Jean-Michel Aubry, Armin von Gunten, Enrique Castelao, Peter Vollenweider, Gerard Waeber, Philippe Conus, and Chin B Eap
Subjects: Medicine, Science
Abstract: Obesity development during psychotropic treatments represents a major health issue in psychiatry. Melanin-concentrating hormone receptor 2 (MCHR2) is a central receptor involved in energy homeostasis. MCHR2 shares its promoter region with MCHR2-AS1, a long antisense non-coding RNA. The aim of this study was to determine whether tagging single nucleotide polymorphisms (tSNPs) of MCHR2 and MCHR2-AS1 are associated with the body mass index (BMI) in the psychiatric and in the general population. The influence of MCHR2 and MCHR2-AS1 tSNPs on BMI was firstly investigated in a discovery psychiatric sample (n1 = 474). Positive results were tested for replication in two other psychiatric samples (n2 = 164, n3 = 178) and in two population-based samples (CoLaus, n4 = 5409; GIANT, n5 = 113809). In the discovery sample, TT carriers of rs7754794C>T had 1.08 kg/m2 (p = 0.04) lower BMI as compared to C-allele carriers. This observation was replicated in an independent psychiatric sample (-2.18 kg/m2; p = 0.009). The association of rs7754794C>T and BMI seemed stronger in subjects younger than 45 years (median of age). In the population-based sample, a moderate association was observed (-0.17 kg/m2; p = 0.02) among younger individuals (
Published: 2015
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12. Associations of serum uric acid and SLC2A9 variant with depressive and anxiety disorders: a population-based study.

Author: Tanica Lyngdoh, Murielle Bochud, Jennifer Glaus, Enrique Castelao, Gerard Waeber, Peter Vollenweider, and Martin Preisig
Subjects: Medicine, Science
Abstract: Limited information exists regarding the association between serum uric acid (SUA) and psychiatric disorders. We explored the relationship between SUA and subtypes of major depressive disorder (MDD) and specific anxiety disorders. Additionally, we examined the association of SLC2A9 rs6855911 variant with anxiety disorders.We conducted a cross-sectional analysis on 3,716 individuals aged 35-66 years previously selected for the population-based CoLaus survey and who agreed to undergo further psychiatric evaluation. SUA was measured using uricase-PAP method. The French translation of the semi-structured Diagnostic Interview for Genetic Studies was used to establish lifetime and current diagnoses of depression and anxiety disorders according to the DSM-IV criteria.Men reported significantly higher levels of SUA compared to women (357±74 µmol/L vs. 263±64 µmol/L). The prevalence of lifetime and current MDD was 44% and 18% respectively while the corresponding estimates for any anxiety disorders were 18% and 10% respectively. A quadratic hockey-stick shaped curve explained the relationship between SUA and social phobia better than a linear trend. However, with regards to the other specific anxiety disorders and other subtypes of MDD, there was no consistent pattern of association. Further analyses using SLC2A9 rs6855911 variant, known to be strongly associated with SUA, supported the quadratic relationship observed between SUA phenotype and social phobia.A quadratic relationship between SUA and social phobia was observed consistent with a protective effect of moderately elevated SUA on social phobia, which disappears at higher concentrations. Further studies are needed to confirm our observations.
Published: 2013
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13. Urotensin-II system in genetic control of blood pressure and renal function.

Author: Radoslaw Debiec, Paraskevi Christofidou, Matthew Denniff, Lisa D Bloomer, Pawel Bogdanski, Lukasz Wojnar, Katarzyna Musialik, Fadi J Charchar, John R Thompson, Dawn Waterworth, Kijoung Song, Peter Vollenweider, Gerard Waeber, Ewa Zukowska-Szczechowska, Nilesh J Samani, David Lambert, and Maciej Tomaszewski
Subjects: Medicine, Science
Abstract: Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p
Published: 2013
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14. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

Author: Robin G Walters, Lachlan J M Coin, Aimo Ruokonen, Adam J de Smith, Julia S El-Sayed Moustafa, Sebastien Jacquemont, Paul Elliott, Tõnu Esko, Anna-Liisa Hartikainen, Jaana Laitinen, Katrin Männik, Danielle Martinet, David Meyre, Matthias Nauck, Claudia Schurmann, Rob Sladek, Gudmar Thorleifsson, Unnur Thorsteinsdóttir, Armand Valsesia, Gerard Waeber, Flore Zufferey, Beverley Balkau, François Pattou, Andres Metspalu, Henry Völzke, Peter Vollenweider, Kári Stefansson, Marjo-Riitta Järvelin, Jacques S Beckmann, Philippe Froguel, and Alexandra I F Blakemore
Subjects: Medicine, Science
Abstract: The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
Published: 2013
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15. Age and gender differences in the social patterning of cardiovascular risk factors in Switzerland: the CoLaus study.

Author: Silvia Stringhini, Brenda Spencer, Pedro Marques-Vidal, Gerard Waeber, Peter Vollenweider, Fred Paccaud, and Pascal Bovet
Subjects: Medicine, Science
Abstract: ObjectivesWe examined the social distribution of a comprehensive range of cardiovascular risk factors (CVRF) in a Swiss population and assessed whether socioeconomic differences varied by age and gender.MethodsParticipants were 2960 men and 3343 women aged 35-75 years from a population-based survey conducted in Lausanne, Switzerland (CoLaus study). Educational level was the indicator of socioeconomic status used in this study. Analyses were stratified by gender and age group (35-54 years; 55-75 years).ResultsThere were large educational differences in the prevalence of CVRF such as current smoking (Δ = absolute difference in prevalence between highest and lowest educational group:15.1%/12.6% in men/women aged 35-54 years), physical inactivity (Δ = 25.3%/22.7% in men/women aged 35-54 years), overweight and obesity (Δ = 14.6%/14.8% in men/women aged 55-75 years for obesity), hypertension (Δ = 16.7%/11.4% in men/women aged 55-75 years), dyslipidemia (Δ = 2.8%/6.2% in men/women aged 35-54 years for high LDL-cholesterol) and diabetes (Δ = 6.0%/2.6% in men/women aged 55-75 years). Educational inequalities in the distribution of CVRF were larger in women than in men for alcohol consumption, obesity, hypertension and dyslipidemia (pConclusionLarge absolute differences in the prevalence of CVRF according to education categories were observed in this Swiss population. The socioeconomic gradient in CVRF tended to be larger in women and in younger persons.
Published: 2012
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16. Specific silencing of the REST target genes in insulin-secreting cells uncovers their participation in beta cell survival.

Author: David Martin, Florent Allagnat, Emilie Gesina, Dorothee Caille, Asllan Gjinovci, Gerard Waeber, Paolo Meda, and Jacques-Antoine Haefliger
Subjects: Medicine, Science
Abstract: The absence of the transcriptional repressor RE-1 Silencing Transcription Factor (REST) in insulin-secreting beta cells is a major cue for the specific expression of a large number of genes. These REST target genes were largely ascribed to a function of neurotransmission in a neuronal context, whereas their role in pancreatic beta cells has been poorly explored. To identify their functional significance, we have generated transgenic mice expressing REST in beta cells (RIP-REST mice), and previously discovered that REST target genes are essential to insulin exocytosis. Herein we characterized a novel line of RIP-REST mice featuring diabetes. In diabetic RIP-REST mice, high levels of REST were associated with postnatal beta cell apoptosis, which resulted in gradual beta cell loss and sustained hyperglycemia in adults. Moreover, adenoviral REST transduction in INS-1E cells led to increased cell death under control conditions, and sensitized cells to death induced by cytokines. Screening for REST target genes identified several anti-apoptotic genes bearing the binding motif RE-1 that were downregulated upon REST expression in INS-1E cells, including Gjd2, Mapk8ip1, Irs2, Ptprn, and Cdk5r2. Decreased levels of Cdk5r2 in beta cells of RIP-REST mice further confirmed that it is controlled by REST, in vivo. Using siRNA-mediated knock-down in INS-1E cells, we showed that Cdk5r2 protects beta cells against cytokines and palmitate-induced apoptosis. Together, these data document that a set of REST target genes, including Cdk5r2, is important for beta cell survival.
Published: 2012
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17. A genome-wide association study of neuroticism in a population-based sample.

Author: Federico C F Calboli, Federica Tozzi, Nicholas W Galwey, Athos Antoniades, Vincent Mooser, Martin Preisig, Peter Vollenweider, Dawn Waterworth, Gerard Waeber, Michael R Johnson, Pierandrea Muglia, and David J Balding
Subjects: Medicine, Science
Abstract: Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 million SNPs imputed with high quality from the Hap Map CEU samples. We found a very small effect of population stratification, corrected using one principal component, and some cryptic kinship that required no correction. NKAIN2 showed suggestive evidence of association with neuroticism as a main effect (p < 10(-6)) and GPC6 showed suggestive evidence for interaction with age (p approximately = 10(-7)). We found support for one previously-reported association (PDE4D), but failed to replicate other recent reports. These results suggest common SNP variation does not strongly influence neuroticism. Our study was powered to detect almost all SNPs explaining at least 2% of heritability, and so our results effectively exclude the existence of loci having a major effect on neuroticism.
Published: 2010
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18. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

Author: J Brent Richards, Dawn Waterworth, Stephen O'Rahilly, Marie-France Hivert, Ruth J F Loos, John R B Perry, Toshiko Tanaka, Nicholas John Timpson, Robert K Semple, Nicole Soranzo, Kijoung Song, Nuno Rocha, Elin Grundberg, Josée Dupuis, Jose C Florez, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Robert Sladek, Yurii Aulchenko, David Evans, Gerard Waeber, Jeanette Erdmann, Mary-Susan Burnett, Naveed Sattar, Joseph Devaney, Christina Willenborg, Aroon Hingorani, Jaquelin C M Witteman, Peter Vollenweider, Beate Glaser, Christian Hengstenberg, Luigi Ferrucci, David Melzer, Klaus Stark, John Deanfield, Janina Winogradow, Martina Grassl, Alistair S Hall, Josephine M Egan, John R Thompson, Sally L Ricketts, Inke R König, Wibke Reinhard, Scott Grundy, H-Erich Wichmann, Phil Barter, Robert Mahley, Y Antero Kesaniemi, Daniel J Rader, Muredach P Reilly, Stephen E Epstein, Alexandre F R Stewart, Cornelia M Van Duijn, Heribert Schunkert, Keith Burling, Panos Deloukas, Tomi Pastinen, Nilesh J Samani, Ruth McPherson, George Davey Smith, Timothy M Frayling, Nicholas J Wareham, James B Meigs, Vincent Mooser, Tim D Spector, and GIANT Consortium
Subjects: Genetics, QH426-470
Abstract: The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
Published: 2009
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19. Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution.

Author: Cecilia M. Lindgren, Iris M. Heid, Joshua C. Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K. Speliotes, Gudmar Thorleifsson, Cristen J. Willer, Blanca M. Herrera, Anne U. Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S. Aulchenko, John C. Chambers, Alexander Drong, Jian'an Luan, Helen N. Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J. Timpson, M. Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J. Bennett, Richard N. Bergman, Lori L. Bonnycastle, Suzannah J. Bumpstead, Stephen J. Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S. F. Doney, Shah Ebrahim, Paul Elliott, Michael R. Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G. Forouhi, Christian Gieger, Harald Grallert, Christopher J. Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S. Havulinna, Albert Hofman, Rolf Holle, John W. Holloway, Thomas Illig, Bo Isomaa, Leonie C. Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G. Mark Lathrop, Debbie A. Lawlor, Massimo Mangino, Wendy L. McArdle, Thomas Meitinger, Mario A. Morken, Andrew P. Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A. Oostra, Colin N. A. Palmer, Felicity Payne, John F. Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S. Sandhu, Laura J. Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M. Stringham, Amy J. Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G. Bragi Walters, Michael N. Weedon, Jacqueline C. M. Witteman, Cuilin Zhang, Weihua Zhang, Mark J. Caulfield, Francis S. Collins, George Davey Smith, Ian N. M. Day, Paul W. Franks, Andrew T. Hattersley, Frank B. Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S. Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D. Morris, Leena Peltonen, Nilesh J. Samani, Timothy D. Spector, David P. Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G. Uitterlinden, Cornelia M. van Duijn, Nicholas J. Wareham, Hugh Watkins for the PROCARDIS consortia, Dawn M. Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J. Hunter, Unnur Thorsteinsdottir, David Schlessinger, H.-Erich Wichmann, Timothy M. Frayling, Gonçalo R. Abecasis, Joel N. Hirschhorn, Ruth J. F. Loos, Kari Stefansson, Karen L. Mohlke, Inês Barroso, and Mark I. McCarthy for the GIANT consortium
Subjects: Genetics, QH426-470
Published: 2009
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20. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

Author: Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, Wellcome Trust Case Control Consortium, Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Francis S Collins, George Davey Smith, Ian N M Day, Paul W Franks, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M van Duijn, Nicholas J Wareham, Hugh Watkins, Procardis Consortia, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke, Inês Barroso, Mark I McCarthy, and Giant Consortium
Subjects: Genetics, QH426-470
Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Published: 2009
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21. Objective polysomnography-based sleep features and major depressive disorder subtypes in the general population

Author: Geoffroy Solelhac, Mathieu Berger, Marie-Pierre F. Strippoli, Nicola Andrea Marchi, Aurélie Stephan, Jean-Marie Petit, Virginie Bayon, Théo Imler, Jose Haba-Rubio, Tifenn Raffray, Peter Vollenweider, Pedro Marques-Vidal, Gerard Waeber, Damien Léger, Francesca Siclari, Pierre A. Geoffroy, Martin Preisig, Raphaël Heinzer, Netherlands Institute for Neuroscience (NIN), and Siclari group
Subjects: Psychiatry and Mental health, Biological Psychiatry
Abstract: Insomnia and its opposite hypersomnia are part of the diagnostic criteria for major depressive disorder (MDD). However, no study has investigated whether the postulated sleep alterations in clinical subtypes of MDD are reflected in polysomnography (PSG)-derived objective sleep measures. The objective of this study was to establish associations between the melancholic, atypical and unspecified subtypes of MDD and objective PSG-based sleep features. This cross-sectional analysis included 1820 community-dwelling individuals who underwent PSG and a semi-structured psychiatric interview to elicit diagnostic criteria for MDD and its subtypes. Adjusted robust linear regression was used to assess associations between MDD subtypes and PSG-derived objective sleep measures. Current melancholic MDD was significantly associated with decreased absolute delta power and sleep efficiency and with increased wake after sleep onset. Remitted unspecified MDD was significantly associated with increased rapid eye movements density. No other significant associations were identified. Our findings reflect that some PSG-based sleep features differed in MDD subtypes compared with no MDD. The largest number of significant differences were observed for current melancholic MDD, whereas only rapid eye movements density could represent a risk factor for MDD as it was the only sleep measure that was also associated with MDD in remitted participants.
Published: 2023

22. Quand les rêves se cristallisent

Author: Gerard Waeber
Published: 2022

23. Wenn Träume wahr werden

Author: Gerard Waeber
Published: 2022

24. Physical activity and sedentary behavior; mechanistic insights and role in disease prevention

Author: Marcel den Hoed, Zhe Wang, Andrew Emmerich, Nicolas Pillon, Timothy Moore, Daiane Hemerich, Marilyn Cornelis, Eugenia Mazzaferro, Siacia Broos, Adam Ameur, Stefania Bandinelli, Joshua Bis, Michael Boehnke, Claude Bouchard, Daniel Chasman, Eco de Geus, Louise Deldicque, Marcus Dörr, Michele Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo Horta, Elina Hypponen, W. Craig Johnson, Sharon Kardia, Lambertus Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Patrik Magnusson, Nicholas Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari North, Claes Ohlsson, Albertine Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda Penninx, Tune Pers, Ozren Polasek, Inga Prokopenko, Charles Rotimi, Nilesh Samani, Xueling Sim, George Davey Smith, Harold Snieder, Thorkild Sorensen, Tim Spector, Nicholas Timpson, Rob van Dam, Nathalie van der Velde, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gerard Waeber, Nick Wareham, David Weir, Erich Wichmann, James Wilson, Andrea Hevener, Anna Krook, Juleen Zierath, Martine Thomis, and Ruth Loos
Abstract: Even though physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Here, we combine data for up to 674,980 individuals from 51 studies in a trans-ancestry meta-analysis of genome-wide association studies for self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA); leisure screen time (LST); sedentary commuting; and sedentary behavior at work. We identify 99 loci that associate with at least one trait. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. Molecular dynamics simulations suggest that the Glu to Ala substitution encoded by rs2229456 (ACTN3) – associated with more MVPA – disrupts salt bridge interactions and makes the alpha actinin 3 filaments more flexible. In isolated type IIA muscle fibers, the Ala-encoding allele is associated with lower maximal force and power during an isometric contraction, suggesting protection from exercise-induced muscle damage. Finally, Mendelian Randomization analyses show that the causal effect of LST on BMI is 2-3 times larger than the effect of body mass index (BMI) on LST, and that beneficial effects of LST and MVPA on several risk factors and diseases are mediated or confounded by BMI. Taken together, our results provide mechanistic insights into the regulation of MVPA and into the role of LST and MVPA in disease prevention. These insights may facilitate the development of tailored physical activity interventions.
Published: 2021

25. How ambient temperature affects mood: an ecological momentary assessment study in Switzerland

Author: Marvin Bundo, Martin Preisig, Kathleen Merikangas, Jennifer Glaus, Julien Vaucher, Gérard Waeber, Pedro Marques-Vidal, Marie-Pierre F. Strippoli, Thomas Müller, Oscar Franco, and Ana Maria Vicedo-Cabrera
Subjects: Climate change, Ambient temperature, Mental health, Mood, Ecological momentary assessment, Industrial medicine. Industrial hygiene, RC963-969, Public aspects of medicine, RA1-1270
Abstract: Abstract Background Recent research has suggested that an increase in temperature can negatively affect mental health and increase hospitalization for mental illness. It is not clear, however, what factors or mechanisms mediate this association. We aimed to (1) investigate the associations between ambient temperatures and bad daily mood, and (2) identify variables affecting the strength of these associations (modifiers) including the time, the day of the week and the year of the mood rating, socio-demographic characteristics, sleep quality, psychiatric disorders and the personality trait neuroticism in the community. Methods Data stemmed from the second follow-up evaluation of CoLaus|PsyCoLaus, a prospective cohort study conducted in the general population of Lausanne (Switzerland). The 906 participants rated their mood level four times a day during seven days using a cell phone app. Mixed-effects logistic regression was used to determine the association between daily maximum temperature and mood level. Participant ID was inserted as a random effect in the model, whereas the time of the day, the day of the week and the year were inserted as fixed effects. Models were controlled for several confounders (socio-demographic characteristics, sleep quality, weather parameters and air pollutants). Stratified analyses were conducted based on socio-demographic characteristics, sleep quality, presence of psychiatric disorders or a high neuroticism. Results Overall, the probability of having a bad mood for the entire day decreased by 7.0% (OR: 0.93: 95% CI 0.88, 0.99) for each 5 °C increase in maximum temperature. A smaller and less precise effect (-3%; OR: 0.97: 95% CI 0.91, 1.03) was found when controlling for sunshine duration. A higher association was found in participants with bipolar disorder (-23%; OR: 0.77: 95% CI 0.51, 1.17) and in participants with a high neuroticism (-13%; OR: 0.87 95% CI 0.80, 0.95), whereas the association was reversed for participants with anxiety (20%; OR: 1.20: 95% CI 0.90, 1.59), depression (18%; OR: 1.18 95% CI 0.94, 1.48) and schizophrenia (193%; OR: 2.93 95% CI 1.17, 7.73). Conclusions According to our findings, rising temperatures may positively affect mood in the general population. However, individuals with certain psychiatric disorders, such as anxiety, depression, and schizophrenia, may exhibit altered responses to heat, which may explain their increased morbidity when exposed to high temperatures. This suggests that tailored public health policies are required to protect this vulnerable population.
Published: 2023
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26. Launching SwissMedPreprints, the Swiss Medical Weekly’s biomedical preprint server

Author: Adriano Aguzzi and Gérard Waeber
Subjects: Medicine
Abstract: No abstract available.
Published: 2023
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27. NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality

Author: Carsten A. Böger, Mathias Gorski, Gearoid M. McMahon, Huichun Xu, Yen-Pei C. Chang, Peter J. van der Most, Gerjan Navis, Ilja M. Nolte, Martin H. de Borst, Weihua Zhang, Benjamin Lehne, Marie Loh, Sian-Tsung Tan, Eric Boerwinkle, Morgan E. Grams, Peggy Sekula, Man Li, Beth Wilmot, James G. Moon, Paul Scheet, Francesco Cucca, Xiangjun Xiao, Leo-Pekka Lyytikäinen, Graciela Delgado, Tanja B. Grammer, Marcus E. Kleber, Sanaz Sedaghat, Fernando Rivadeneira, Tanguy Corre, Zoltan Kutalik, Sven Bergmann, Carrie M. Nielson, Priya Srikanth, Alexander Teumer, Martina Müller-Nurasyid, Anne Catharina Brockhaus, Arne Pfeufer, Wolfgang Rathmann, Annette Peters, Martha Matsumoto, Mariza de Andrade, Elizabeth J. Atkinson, Cassianne Robinson-Cohen, Ian H. de Boer, Shih-Jen Hwang, Iris M. Heid, Martin Gögele, Maria Pina Concas, Toshiko Tanaka, Stefania Bandinelli, Mike A. Nalls, Andrew Singleton, Salman M. Tajuddin, Adebowale Adeyemo, Jie Zhou, Ayo Doumatey, Shannon McWeeney, Joanne Murabito, Nora Franceschini, Michael Flessner, Michael Shlipak, James G. Wilson, Guanjie Chen, Charles N. Rotimi, Alan B. Zonderman, Michele K. Evans, Luigi Ferrucci, Olivier Devuyst, Mario Pirastu, Alan Shuldiner, Andrew A. Hicks, Peter Paul Pramstaller, Bryan Kestenbaum, Sharon L.R. Kardia, Stephen T. Turner, LifeLines Cohort Study, Tamara Ellefson Briske, Christian Gieger, Konstantin Strauch, Christa Meisinger, Thomas Meitinger, Uwe Völker, Matthias Nauck, Henry Völzke, Peter Vollenweider, Murielle Bochud, Gerard Waeber, Mika Kähönen, Terho Lehtimäki, Winfried März, Abbas Dehghan, Oscar H. Franco, Andre G. Uitterlinden, Albert Hofman, Herman A. Taylor, John C. Chambers, Jaspal S. Kooner, Caroline S. Fox, Robert Hitzemann, Eric S. Orwoll, Cristian Pattaro, David Schlessinger, Anna Köttgen, Harold Snieder, Afshin Parsa, David M. Cohen, Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Life Course Epidemiology (LCE), Value, Affordability and Sustainability (VALUE), Groningen Institute for Organ Transplantation (GIOT), Böger, Carsten A., Gorski, Mathia, Mcmahon, Gearoid M., Xu, Huichun, Chang, Yen Pei C., Van Der Most, Peter J., Navis, Gerjan, Nolte, Ilja M., De Borst, Martin H., Zhang, Weihua, Lehne, Benjamin, Loh, Marie, Tan, Sian Tsung, Boerwinkle, Eric, Grams, Morgan E., Sekula, Peggy, Li, Man, Wilmot, Beth, Moon, James G., Scheet, Paul, Cucca, Francesco, Xiao, Xiangjun, Lyytikäinen, Leo Pekka, Delgado, Graciela, Grammer, Tanja B., Kleber, Marcus E., Sedaghat, Sanaz, Rivadeneira, Fernando, Corre, Tanguy, Kutalik, Zoltan, Bergmann, Sven, Nielson, Carrie M., Srikanth, Priya, Teumer, Alexander, Müller Nurasyid, Martina, Brockhaus, Anne Catharina, Pfeufer, Arne, Rathmann, Wolfgang, Peters, Annette, Matsumoto, Martha, De Andrade, Mariza, Atkinson, Elizabeth J., Robinson Cohen, Cassianne, De Boer, Ian H., Hwang, Shih Jen, Heid, Iris M., Gögele, Martin, Concas, MARIA PINA, Tanaka, Toshiko, Bandinelli, Stefania, Nalls, Mike A., Singleton, Andrew, Tajuddin, Salman M., Adeyemo, Adebowale, Zhou, Jie, Doumatey, Ayo, Mcweeney, Shannon, Murabito, Joanne, Franceschini, Nora, Flessner, Michael, Shlipak, Michael, Wilson, James G., Chen, Guanjie, Rotimi, Charles N., Zonderman, Alan B., Evans, Michele K., Ferrucci, Luigi, Devuyst, Olivier, Pirastu, Mario, Shuldiner, Alan, Hicks, Andrew A., Pramstaller, Peter Paul, Kestenbaum, Bryan, Kardia, Sharon L. R., Turner, Stephen T., Study, Lifelines Cohort, Briske, Tamara Ellefson, Gieger, Christian, Strauch, Konstantin, Meisinger, Christa, Meitinger, Thoma, Völker, Uwe, Nauck, Matthia, Völzke, Henry, Vollenweider, Peter, Bochud, Murielle, Waeber, Gerard, Kähönen, Mika, Lehtimäki, Terho, März, Winfried, Dehghan, Abba, Franco, Oscar H., Uitterlinden, Andre G., Hofman, Albert, Taylor, Herman A., Chambers, John C., Kooner, Jaspal S., Fox, Caroline S., Hitzemann, Robert, Orwoll, Eric S., Pattaro, Cristian, Schlessinger, David, Köttgen, Anna, Snieder, Harold, Parsa, Afshin, and Cohen, David M.
Subjects: 0301 basic medicine, medicine.medical_specialty, hyponatremia, Body water, Water-Electrolyte Imbalance, PROTEIN, human genetics, Genome-wide association study, Biology, 03 medical and health sciences, Plasma, NFAT5, Internal medicine, Gene expression, Genetic variation, Transcriptional regulation, medicine, Humans, human genetic, CELL-TYPES, GENE-EXPRESSION, Genetics, IDENTIFICATION, hypernatremia, Sodium-Bicarbonate Symporter, Sodium-Bicarbonate Symporters, Sodium, PRIMARY-CARE, 1103 Clinical Sciences, General Medicine, Urology & Nephrology, water-electrolyte balance, Plasma osmolality, Human Genetics, Hypernatremia, Hyponatremia, Water-electrolyte Balance, 030104 developmental biology, Endocrinology, Basic Research, NEPHROGENIC DIABETES-INSIPIDUS, Genome-Wide Association Study, Genetic Loci, Nephrology, Expression quantitative trait loci, TRANSCRIPTION FACTOR-BINDING, INAPPROPRIATE ANTIDIURESIS, INTRONIC ENHANCERS, Human
Abstract: Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P-6. Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 3 x 10-5), with combined stages 1 and 2 genomewide significance of P=5.6 x 10-10. Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous systemand relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.
Published: 2017

28. FTO genotype is associated with phenotypic variability of body mass index

Author: Jean-Claude Tardif, Caroline Hayward, Alan James, Jeffrey R. O'Connell, Gemma Cadby, Lyle J. Palmer, Alexander Teumer, Tõnu Esko, Georg Homuth, Karol Estrada, Peter Vollenweider, M. Carola Zillikens, Anneli Pouta, Anuj Goel, Aaron Isaacs, Charles S. White, Lindsay L. Waite, Joseph E. Powell, Laura M. Yerges-Armstrong, Unnur Thorsteinsdottir, Mary F. Feitosa, Sarah E. Medland, Jana V. van Vliet-Ostaptchouk, Ivana Kolcic, Joel Eriksson, Sita H. Vermeulen, Jennifer L. Bragg-Gresham, L. Adrienne Cupples, Folkert W. Asselbergs, Gerard Waeber, Marjo-Riitta Järvelin, Krista Fischer, Peter P. Pramstaller, Gudmar Thorleifsson, James F. Wilson, Jonathan Tyrer, Kevin B. Jacobs, Jacqueline M. Vink, Jennifer Jolley, Tatijana Zemunik, Sekar Kathiresan, Michael Stumvoll, Daniele Cusi, Inga Prokopenko, Lynda M. Rose, Reedik Mägi, Annette Peters, Sonja I. Berndt, David Schlessinger, Sarah H Wild, Tim D. Spector, Bruce M. Psaty, Cameron D. Palmer, Eco J. C. de Geus, André G. Uitterlinden, Tamara B. Harris, Anubha Mahajan, Caroline S. Fox, Ben A. Oostra, Francis S. Collins, Paul M. Ridker, Albert V. Smith, Barbara McKnight, Christian Hengstenberg, Grant W. Montgomery, Zoltán Kutalik, Gerjan Navis, Jan A. Staessen, Larry D. Atwood, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Carlo Sidore, Ilja M. Nolte, Carlos Iribarren, Harold Snieder, Jing Hua Zhao, Veronique Vitart, Jonathan Stephens, Nancy L. Heard-Costa, Anne U. Jackson, Nicholas G. Martin, Heikki V. Huikuri, Melanie M. van der Klauw, Alan R. Shuldiner, Vilmundur Gudnason, Jouke-Jan Hottenga, Daniel I. Chasman, Anke Tönjes, Kari Stefansson, Ulrich John, Arthur W. Musk, Jian Yang, Kari E. North, Mark I. McCarthy, Niek Verweij, Jennifer E. Huffman, Massimo Mangino, Per Hall, Michael E. Goddard, Joel N. Hirschhorn, Guillaume Lettre, Nicola S. Foad, Jennie Hui, Alan F. Wright, Karen Kapur, Jacqueline C. M. Witteman, David Hadley, Eric Boerwinkle, Pim van der Harst, Dorret I. Boomsma, Harry Campbell, Anders Hamsten, Michael Boehnke, Leif Groop, Serena Sanna, Albert Hofman, Wendy L. McArdle, Andres Metspalu, Elizabeth K. Speliotes, Pamela A. F. Madden, M. Juhani Junttila, Igor Rudan, Guo Li, Andreas Ziegler, Keri L. Monda, John Beilby, Lambertus A. Kiemeney, Dale R. Nyholt, Lenore J. Launer, Karen L. Mohlke, Klaus Stark, Hugh Watkins, Fernando Rivadeneira, Lina Zgaga, Sophie R. Wang, Jian'an Luan, Peter M. Visscher, Claes Ohlsson, Marika Kaakinen, Ayse Demirkan, Gonneke Willemsen, Erik Ingelsson, Michael A. Province, Jacques S. Beckmann, Brenda W. J. H. Penninx, Nicholas J. Wareham, Themistocles L. Assimes, Stephen J. Chanock, Andrew C. Heath, Ruth J. F. Loos, Talin Haritunians, Gonçalo R. Abecasis, Timothy M. Frayling, Jaana Laitinen, Ingrid B. Borecki, Jeanette Erdmann, Mattias Lorentzon, Michael Preuss, Francesca Frau, Sabine Schipf, Carolina Medina-Gomez, Kay-Tee Khaw, Andrew A. Hicks, William G. Hill, Heribert Schunkert, Henrik Grönberg, Cornelia M. van Duijn, Samuli Ripatti, Stefan Schreiber, Ozren Polasek, David P. Strachan, Biological Psychology, Molecular Cell Physiology, Amsterdam Global Change Institute, Chemistry and Biology, Clinical Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Cardiovascular Centre (CVC), Epidemiology, Public Health, Erasmus MC other, Clinical Genetics, Hematology, Internal Medicine, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Psychiatry, and EMGO - Lifestyle, overweight and diabetes
Subjects: Male, SELECTION, Netherlands Twin Register (NTR), LOCI, CHILDHOOD, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], VARIANTS, FTO gene, Body Mass Index, 0302 clinical medicine, Genotype, ADULT OBESITY, 2. Zero hunger, Genetics, 0303 health sciences, Multidisciplinary, GENETIC-VARIATION, 3. Good health, Phenotype, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Female, Co-Repressor Proteins, TRAITS, Nerve Tissue Proteins, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Humans, GENOME-WIDE ASSOCIATION, SDG 2 - Zero Hunger, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Genetic association, Genetic Variation, Proteins, nutritional and metabolic diseases, FTO, obesity, body mass index, Body Height, Repressor Proteins, PHYSICAL-ACTIVITY, ENVIRONMENTAL SENSITIVITY, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000. ispartof: Nature vol:490 issue:7419 pages:267-272 ispartof: location:England status: published
Published: 2016

29. Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans

Author: Stela, McLachlan, Claudia, Giambartolomei, Jon, White, Pimphen, Charoen, Andrew, Wong, Chris, Finan, Jorgen, Engmann, Tina, Shah, Micha, Hersch, Clara, Podmore, Alana, Cavadino, Barbara J, Jefferis, Caroline E, Dale, Elina, Hypponen, Richard W, Morris, Juan P, Casas, Meena, Kumari, Yoav, Ben-Shlomo, Tom R, Gaunt, Fotios, Drenos, Claudia, Langenberg, Diana, Kuh, Mika, Kivimaki, Rico, Rueedi, Gerard, Waeber, Aroon D, Hingorani, Jacqueline F, Price, Ann P, Walker, and UCLEB Consortium
Subjects: DNA Replication, Europe, Erythrocytes, hemic and lymphatic diseases, Quantitative Trait Loci, Ethnicity, Humans, Correction, ABO Blood-Group System/genetics, DNA Replication/genetics, Erythrocytes/physiology, Ethnic Groups, Genome-Wide Association Study, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Polymorphism, Single Nucleotide, ABO Blood-Group System
Abstract: Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.
Published: 2016

30. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Author: John R. B. Perry, James B. Meigs, José Dupuis, Luigi Ferrucci, Johan G. Eriksson, Vilmundur Gudnason, Eric J.G. Sijbrands, Jeanette S. Andrews, Jonna L. Grimsby, Lawrence F. Bielak, Peter Kovacs, Panos Deloukas, Marijana Peričić, Johannes H. Smit, Ruth J. F. Loos, Gonneke Willemsen, Eric Boerwinkle, Ben A. Oostra, Manuel Serrano-Ríos, Alena Stančáková, Meena Kumari, Antti Jula, Michael Marmot, Caroline S. Fox, Simon Heath, Guo Li, Ola Hansson, Gerard Waeber, Anne U. Jackson, Nicholas L. Smith, Markku Laakso, George Dedoussis, Aarno Palotie, Sara M. Willems, John F. Peden, Elisabeth Widen, Caroline Hayward, Alan F. Wright, Claes Ladenvall, May E. Montasser, María Teresa Martínez-Larrad, Peter Vollenweider, Louis Pérusse, Tamara B. Harris, Wen Hong L. Kao, Danijela Budimir, Denis Rybin, David B. Savage, Michael A. Province, Alisa K. Manning, Bruna Gigante, Najaf Amin, Lenore J. Launer, Naveed Sattar, Lori L. Bonnycastle, Göran Hallmans, Jeffrey R. O'Connell, Stéphane Lobbens, Jacques S. Beckmann, Gemma Cadby, J. Wouter Jukema, Maria Dimitriou, Michael Stumvoll, Max Vikström, Rona J. Strawbridge, Hugh Watkins, Lyle J. Palmer, Johanna Kuusisto, Aimo Ruokonen, Hanieh Yaghootkar, Yan V. Sun, Inês Barroso, Amy J. Swift, Nancy L. Pedersen, Lars Lind, Mladen Boban, Nita G. Forouhi, Ken K. Ong, Ivana Kolcic, Anke Tönjes, Timothy M. Frayling, Paul W. Franks, Narisu Narisu, Karin Leander, Serge Hercberg, Diana Zelenika, Sharon L.R. Kardia, Min A. Jhun, Marjo-Riitta Järvelin, Stella Trompet, Jaakko Kaprio, Toshiko Tanaka, David S. Siscovick, Toby Johnson, Cornelia M. van Duijn, Veikko Salomaa, Jose C. Florez, James F. Wilson, Leena Peltonen, Pilar Galan, Robert Clarke, Andrew A. Hicks, Claudia Langenberg, Anders Hamsten, David Couper, Albert Hofman, Dawn M. Waterworth, John Blangero, James S. Pankow, Nabila Bouatia-Naji, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Valeriya Lyssenko, Leif Groop, Brenda W.J.H. Penninx, Ching-Ti Liu, Anuj Goel, Marina Pehlić, Michael Boehnke, Mika Kivimäki, Maria Sabater-Lleal, Emil Rehnberg, Ingrid B. Borecki, Ozren Polasek, Eco J. C. de Geus, Peter P. Pramstaller, Igor Rudan, Richard M. Watanabe, Pierre Meneton, Iva Miljkovic, Vincent Mooser, G. Mark Lathrop, John Beilby, Laura J. Rasmussen-Torvik, Arturo Corbató-Anchuelo, Yvonne Böttcher, Richard N. Bergman, Daniel R. Barnes, Paul C. D. Johnson, Mustafa Atalay, Aroon D. Hingorani, Olga D. Carlson, Perttu Salo, Jacqueline C.M. Witteman, Udo Seedorf, Timo Saaristo, Jian'an Luan, Nicholas J. Wareham, Gudny Eiriksdottir, Matti Uusitupa, Yongmei Liu, Jaakko Tuomilehto, Yurii S. Aulchenko, Peter Schwarz, Robert A. Scott, Lina Zgaga, Joseph Hung, Reedik Mägi, Maria Grazia Franzosi, Eric J. Brunner, Claude Bouchard, Ian Ford, Francis S. Collins, Ulf de Faire, Benjamin F. Voight, Erik Ingelsson, Mario A. Morken, Stefania Bandinelli, Nicole L. Glazer, Dmitry Shungin, Lars Lannfelt, André G. Uitterlinden, Tatijana Zemunik, Markus Perola, Kenneth Rice, Veronique Vitart, Kerrin S. Small, Jouke-Jan Hottenga, Han Chen, Jerome I. Rotter, Philippe Froguel, Karen L. Mohlke, Marie-Claude Vohl, Dorret I. Boomsma, Harry Campbell, Peter S. Chines, Pau Navarro, Vasiliki Lagou, Albert V. Smith, Kathleen Stirrups, Josephine M. Egan, Alan R. Shuldiner, Katri Räikkönen, Inga Prokopenko, Ping An, Rainer Rauramaa, Beverley Balkau, Thor Aspelund, Eleanor Wheeler, Mariza de Andrade, Richa Saxena, Jari Lahti, Cécile Lecoeur, Timo A. Lakka, Jennie Hui, Michael R. Erdos, Stavroula Kanoni, Kirsten Ohm Kyvik, Bengt Sennblad, Sarah H. Wild, Patricia A. Peyser, Patrik K. E. Magnusson, Claire Bellis, Elodie Eury, Jaana Lindström, Boston University [Boston] (BU), Broad Institute of Harvard and MIT, Partenaires INRAE, Massachusetts General Hospital, Massachusetts General Hospital [Boston], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), Department of Medicine, Université de Sherbrooke (UdeS), Addenbrooke's Hospital, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Center [Boston] (BIDMC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Department of Epidemiology, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-Center for Social Epidemiology and Population Health, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], The Wellcome Trust Centre for Human Genetics [Oxford], The Netherlands Cancer Institute, Ontario Institute for Cancer Research, Mount Sinai Hospital [Toronto, Canada] (MSH), VU University Amsterdam, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Michigan System, Queen Mary University of London (QMUL), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Diabetes Centre, Lund University, University of Helsinki, Wake Forest School of Medicine, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, University of Maryland School of Medicine, University of Maryland System, University of Edinburgh, University of Exeter, Department of Twin Research and Genetic Epidemiology, King's College London, London, Northwestern University [Evanston], National Institute of Health and Welfare, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Lund University Diabetes Centre, Umeå University, National Institutes of Health, Centre for Medical Systems Biology, Netherlands Genomics Initiative, Washington University in Saint Louis (WUSTL), Department of Health Sciences Research, Mayo Clinic, Wake Forest University, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, Institute of Biomedicine, Physiology, University of Eastern Finland, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S 1018, Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Department of Medical Genetics, Université de Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois (CHUV), Queen Elizabeth II Medical Centre, Research Institute, University of Southern California (USC), University of Split, The University of Texas Health Science Center at Houston (UTHealth), Leipzig University, Pennington Biomedical Research Center, Department of Epidemiology & Public Health, University College of London [London] (UCL), San Carlos Clinical Hospital, University of North Carolina, Harokopio University, National Institute on Aging, Folkhälsan Research Centre, Vaasa Central Hospital, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Epidemiology, Immunology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Ophthalmology, Internal Medicine, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA)
Subjects: Blood Glucose, Netherlands Twin Register (NTR), medicine.medical_treatment, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Type 2 diabetes, SUSCEPTIBILITY, Body Mass Index, GLUCOSE, Blood Glucose/metabolism, Cholesterol, HDL/metabolism, Diabetes Mellitus, Type 2/genetics, Genome-Wide Association Study, Humans, Insulin/metabolism, Insulin Resistance/genetics, Polymorphism, Single Nucleotide, 0302 clinical medicine, Insulin, 2. Zero hunger, Genetics, 0303 health sciences, COMMON VARIANTS, 3. Good health, ENVIRONMENT INTERACTION, OBESITY, CORONARY-ARTERY-DISEASE, medicine.medical_specialty, 030209 endocrinology & metabolism, Accounting, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes mellitus, medicine, 030304 developmental biology, Genetic association, Glycemic, loci, SNP, insulin, business.industry, Cholesterol, HDL, medicine.disease, Obesity, POLYMORPHISM, ASSOCIATION ANALYSIS, Endocrinology, Diabetes Mellitus, Type 2, TYPE-2 DIABETES RISK, Insulin Resistance, business
Abstract: Group Authors : DIAGRAM Consortium MUTHER Consortium variants influencing fasting glycemic traits and insulin resistance Seuls les 100 premiers auteurs ont été conservés dans la publication. La liste complète des auteurs et des des affiliations est disponible sur la publication https://www.nature.com/articles/ng.2274.pdf p. 667-669.; International audience; Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Published: 2012

31. Investigating acceptability of a training programme in precision medicine for frontline healthcare professionals: a mixed methods study

Author: Sharon Mitchell, Evrim Jaccard, Felix Michael Schmitz, Elianne von Känel, Prune Collombet, Jacques Cornuz, Gérard Waeber, Idris Guessous, and Sissel Guttormsen
Subjects: Precision medicine, Continuing professional development, Conceptual frameworks, Implementation Science outcomes, Special aspects of education, LC8-6691, Medicine
Abstract: Abstract Background Precision Medicine offers tailored prevention, diagnosis, treatment and management to patients that considers genomics, lifestyle and environmental factors. If implementation of Precision Medicine is to advance, effective, focused upskilling of frontline healthcare professionals through quality continuing professional development is needed. This study reports on an evidence-based approach to needs assessment to investigate the current level of knowledge of Precision Medicine, acceptable content for training, the perceived potential of a more precision approach to patient care and motivation to participate in a training programme among pharmacists, advanced practice nurses and general practitioners. Investigating perceived needs can avoid a top-down approach and support a design that is fit for purpose to targeted professions. Methods This study reports on 2 focus groups (n = 12) delivered in French and German with equal professional participation of the targeted professions. The research objectives were investigated in two phases. During the first phase, a literature review and expert consultations were conducted to develop a definition of PM, patient cases and content for training. In a second phase, these investigations were further explored using focus groups to investigate acceptable learning objectives, the potential of PM to relevant professions and motivation of participants. Quantitative investigations using rating scales and visual analogues were incorporated. The focus groups were audio recorded, transcribed by intelligent verbatim and translated to English. NVivo was used for data analysis and interpretation following a hybrid approach using the Framework Method and thematic analysis. The analytical framework, Implementation Science, was applied to organise and present research data. Results Precision Medicine is considered a new topic area, largely unfamiliar to frontline healthcare professionals.. There was acceptance of a more precision approach to care among all participants with perceived positive implications for patients. Valuable insight was gathered on acceptable content and form for training. All participants expressed concerns on readiness within their professions which included an insufficient system infrastructure, a lack of time to attend needed training, a lack of clarity for use in practice and the time needed to build a support network. Conclusions A precision approach to patient care is on the horizon for health care professionals not only in hospital settings but also at the community level. Our results conclude that an adaptable and flexible training programme in PM is timely, contextually relevant and conducive to the needs of targeted health professions for successful implementation. A training programme in PM will require support across sectors and stakeholders, supporting insurance models, educated patients and integrated care supported by innovative technology. Implementation Science outcomes are a useful strategy towards design of an effective training programme that can have measurable impact in practice.
Published: 2022
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32. Réponse à l’éditorial intitulé « Back to Bedside!»

Author: Gerard Waeber
Subjects: General Medicine
Published: 2018

33. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author: Kenneth Rice, Amy J. Swift, Veronique Vitart, Lu Qi, Kaisa Silander, Olivier Le Bacquer, Laura Crisponi, David S. Siscovick, Bo Isomaa, Anne U. Jackson, Anke Tönjes, Richard N. Bergman, Rosa Maria Roccasecca, Luigi Ferrucci, Narisu Narisu, Kari Stefansson, Holly E. Syddall, Giuseppe Paolisso, Kim L. Ward, Paul Elliott, Scott M. Grundy, Paul Johnson, Jerome I. Rotter, Philippe Froguel, James B. Meigs, George Davey Smith, Andrew T. Hattersley, Leena Peltonen, Eric J.G. Sijbrands, Serena Sanna, María TeresaMartínez-Larrad, David Altshuler, Harald Grallert, Caroline S. Fox, Nita G. Forouhi, Dorret I. Boomsma, Harry Campbell, Jean Tichet, Angelo Scuteri, Aroon D. Hingorani, Daniel S. Pearson, Meena Kumari, Silvia Naitza, Shah Ebrahim, Manjinder S. Sandhu, Jose C. Florez, Cyrus Cooper, David M. Nathan, Joseph Hung, Fredrik Karpe, Ozren Polasek, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Abbas Dehghan, Udo Seedorf, Beverley M. Shields, Antti Jula, Pau Navarro, Josephine M. Egan, Rune R. Frants, Leif Groop, Gunnar Sigursson, Seppo Koskinen, Vincent Mooser, François Pattou, Jing Hua Zhao, Irene Pichler, John F. Peden, Göran Hallmans, Toshiko Tanaka, Ruth J. F. Loos, Peter Kovacs, Andrew D. Morris, Cécile Lecoeur, Jeffrey R. O'Connell, Massimo Mangino, Nicole Vogelzangs, Rhian Gwilliam, Gordon H. Williams, Carina Zabena, Naomi Hammond, Amélie Bonnefond, Björn Zethelius, Joachim Spranger, Nancy L. Pedersen, Christopher J. Groves, Nicholas J. Timpson, George Dedoussis, Veikko Salomaa, Peter Henneman, Andrew Walley, Serge Hercberg, Ian N. M. Day, Simon Heath, Matt Neville, Alex S. F. Doney, Robert Clarke, Olov Rolandsson, Panos Deloukas, Eric Boerwinkle, Y. AnteroKesaniemi, Mike Sampson, Gerard Waeber, Sven Bergmann, Ben A. Oostra, Manuel Serrano-Ríos, Mandy van Hoek, Christine Cavalcanti-Proença, Anna L. Gloyn, Ulla Sovio, Andrew P. Morris, Anneli Pouta, Amanda J. Bennett, Paul Scheet, Peter Schwarz, Jaakko Tuomilehto, Hugh Watkins, Johanna Kuusisto, Denis Rybin, Anna LiisaHartikainen, Maria GraziaFranzosi, Unnur Thorsteinsdottir, Rafn Benediktsson, Alan F. Wright, Colin N. Apalmer, Anuj Goel, Yavuz Ariyurek, Lars Lind, Robert Sladek, Stefan R. Bornstein, Reedik Mägi, Laila Simpson, Tim D. Spector, Paul W. Franks, Nicholas L. Smith, John R. B. Perry, Peter Vollenweider, Suzannah Bumpstead, Ruth E. Pakyz, Christa Meisinger, Alan R. Shuldiner, Josée Dupuis, Man Li, Eric J. Brunner, Francis S. Collins, Torben Hansen, James F. Wilson, Guangju Zhai, Igor Rudan, Nicole L. Glazer, Marco Orrù, Pierre Meneton, Knut Borch-Johnsen, Eleanor Wheeler, Gonçalo R. Abecasis, Mark I. McCarthy, Jouke JanHottenga, Inga Prokopenko, Ping An, Jérôme Delplanque, Albert Hofman, Andrew B. Singleton, Gabe Crawford, Thomas A. Buchanan, Avan Aihie Sayer, Richard M. Watanabe, David Schlessinger, A C Fedson, André G. Uitterlinden, Frank B. Hu, Jaqueline C. MWitteman, Dhiraj Varma, Ingrid B. Borecki, Sutapa Mukherjee, Murielle Bochud, Barbara Thorand, Christian Gieger, Lori L. Bonnycastle, Stephen J. Sharp, Markus Perola, Caroline Hayward, Kristin Ardlie, J. Graessler, Robert W. Mahley, Toby Johnson, Jian'an Luan, Joshua C. Randall, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Valgerdur Steinthorsdottir, Yurii S. Aulchenko, G. Mark Lathrop, Christian Dina, Eleftheria Zeggini, Cecilia M. Lindgren, Stavroula Kanoni, Timothy M. Frayling, Dawn M. Waterworth, Marika Kaakinen, Timo T. Valle, Diana Zelenika, Yii Der IdaChen, Angela Silveira, Nigel W. Rayner, Aimo Ruokonen, Yun Li, Cristian Pattaro, Annelli Sandbæk, Richa Saxena, Danielle Posthuma, Steven A. McCarroll, Niels Grarup, Samy Hadjadj, Pilar Galan, Xijing Han, Lyle J. Palmer, Ulf Gyllensten, Peter P. Pramstaller, Manuela Uda, Jarred B. McAteer, Brenda W.J.H. Penninx, Debbie A Lawlor, Torben Jørgensen, Beatrice Knight, Yvonne Böttcher, Claudia Langenberg, Nicole Soranzo, Ghislain Rocheleau, Erik Ingelsson, Mario A. Morken, Michael Roden, Felicity Payne, David R. Hillman, Michael Marmot, Karen L. Mohlke, Heather M. Stringham, Bruce M. Psaty, Gudmar Thorleifsson, Yoav Ben-Shlomo, Inês Barroso, W. H. Linda Kao, James S. Pankow, Valeriya Lyssenko, Nicholas J. Wareham, Tiinamaija Tuomi, Ann ChristineSyvänen, Braxton D. Mitchell, Alisa K. Manning, Mika Kivimäki, Peter Wagner, Praveen Sethupathy, G. BragiWalters, Jaakko Kaprio, Kijoung Song, Marjo Riitta-Järvelin, Michael A. Province, Andrew A. Hicks, Marilyn C. Cornelis, Sarah H. Wild, David Meyre, Guillaume Charpentier, Patrik K. E. Magnusson, David Melzer, Jennie Hui, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Michael R. Erdos, Oluf Pedersen, Andreas Pfeiffer, Augustine Kong, Christian Herder, Laura J. Scott, John W. GYarnell, Kirsten Ohm Kyvik, Beverley Balkau, Antje Fischer-Rosinsky, Gonneke Willemsen, Thomas Illig, Neelam Hassanali, Markku Laakso, Michael Boehnke, John Beilby, Christopher S. Franklin, Fernando Rivadeneira, M. Carola Zillikens, Michael N. Weedon, Antonio Cao, Mark E. Cooper, Simon C. Potter, Eco J. C. de Geus, H.-Erich Wichmann, Amanda F. Elliott, Lachlan J. McOin, Sophie Visvikis-Siest, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Peter S. Chines, Nabila Bouatia-Naji, Medical Research Council (MRC), Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Ophthalmology, Epidemiology, Clinical Genetics, Dermatology, Internal Medicine, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Human genetics, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, and NCA - Anxiety & Depression
Subjects: Blood Glucose, Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Type 2 diabetes, CIRCADIAN CLOCK, TRIGLYCERIDE LEVELS, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, Databases, Genetic, Homeostasis, GENETICS & HEREDITY, Anders Hamsten on behalf of Procardis Consortium, Child, Genetics, PLASMA-GLUCOSE, 0303 health sciences, Glucokinase regulatory protein, COMMON VARIANTS, 11 Medical And Health Sciences, Fasting, MAGIC investigators, 3. Good health, MODEL ASSESSMENT, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, ESSENTIAL COMPONENTS, Adolescent, DNA Copy Number Variations, Alleles, Blood Glucose/genetics, Blood Glucose/metabolism, DNA Copy Number Variations/genetics, Diabetes Mellitus, Type 2/genetics, Fasting/blood, Gene Expression Regulation, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis/genetics, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Quantitative Trait, Heritable, Reproducibility of Results, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, DIAGRAM Consortium, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, Fasting glucose, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, genome wide association study, glucose, diabetes type 2, medicine, GIANT Consortium, Allele, GENOME-WIDE ASSOCIATION, Global BPgen Consortium, 030304 developmental biology, Glycemic, Science & Technology, genome-wide association beta-cell dysfunction plasma-glucose insulin-secretion triglyceride levels essential components model assessment common variants circadian clock disease risk, DISEASE RISK, 06 Biological Sciences, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, biology.protein, BETA-CELL DYSFUNCTION, Developmental Biology
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46, 186 nondiabetic participants. Follow-up of 25 loci in up to 76, 558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Published: 2010
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34. Strong Impact of Smoking on Multimorbidity and Cardiovascular Risk Among Human Immunodeficiency Virus-Infected Individuals in Comparison With the General Population

Author: Hasse, Barbara, Tarr, Philip E, Marques-Vidal, Pedro, Waeber, Gerard, Preisig, Martin, Mooser, Vincent, Valeri, Fabio, Djalali, Sima, Rauch, Andri, Bernasconi, Enos, Calmy, Alexandra, Cavassini, Matthias, Vernazza, Pietro, Battegay, Manuel, Weber, Rainer, Senn, Oliver, Vollenweider, Peter, Ledergerber, Bruno, Aubert, V, Barth, J, Battegay, M, Bernasconi, E, Böni, J, Bucher, H C, Burton-Jeangros, C, Calmy, A, Cavassini, M, Egger, M, Elzi, L, Fehr, J, Fellay, J, Furrer, Hansjakob, Fux, C A, Gorgievski, Meri, Günthard, H, Haerry, D, Hasse, B, Hirsch, H H, Hösli, I, Kahlert, C, Kaiser, L, Keiser, O, Klimkait, T, Kouyos, R, Kovari, H, Ledergerber, B, Martinetti, G, Martinez de Tejada, B, Metzner, K, Müller, N, Nadal, D, Pantaleo, G, Regenass, S, Rickenbach, M, Rudin, C, Schöni-Affolter, F, Schmid, P, Schultze, D, Schüpbach, J, Speck, R, Stähelin, Cornelia Johanna, Tarr, P, Telenti, A, Trkola, A, Vernazza, P, Weber, R, Yerly, S, Jean-Michel, Aubry, Murielle, Bochud, Jean Michel, Gaspoz, Christoph, Hock, Thomas, Lüscher, Pedro, Marques Vidal, Vincent, Mooser, Fred, Paccaud, Martin, Preisig, Peter, Vollenweider, Roland, Von Känel, Aidacic, Vladeta, Gerard, Waeber, Jürg, Beriger, Markus, Bertschi, Heinz, Bhend, Martin, Büchi, Hans-Ulrich, Bürke, Ivo, Bugmann, Reto, Cadisch, Isabelle, Charles, Corinne, Chmiel, Sima, Djalali, Peter, Duner, Simone, Erni, Andrea, Forster, Markus, Frei, Claudius, Frey, Jakob, Frey, Ali, Gibreil Musa, Matthias, Günthard, Denis, Haller, Marcel, Hanselmann, Walter, Häuptli, Simon, Heininger, Felix, Huber, Paul, Hufschmid, Eva, Kaiser, Vladimir, Kaplan, Daniel, Klaus, Stephan, Koch, Beat, Köstner, Benedict, Kuster, Heidi, Kuster, Vesna, Ladan, Giovanni, Lauffer, Werner, Leibundgut Hans, Phillippe, Luchsinger, Severin, Lüscher, Christoph, Maier, Jürgen, Martin, Damian, Meli, Werner, Messerli, Titus, Morger, Valentina, Navarro, Jakob, Rizzi, Thomas, Rosemann, Hana, Sajdl, Frank, Schindelek, Georg, Schlatter, Oliver, Senn, Pietro, Somaini, Jacques, Staeger, Alfred, Staehelin, Alois, Steinegger, Claudia, Steurer, Othmar, Suter, Phuoc, Truong The, Marco, Vecellio, Alessandro, Violi, René, Von Allmen, Hans, Waeckerlin, Fritz, Weber, Johanna, Weber-Schär, Joseph, Widler, Marco, Zoller, Burton-Jeangros, Claudine, Kaiser, Laurent, Aubry, Jean-Michel, Bochud, Murielle, Gaspoz, Jean-Michel, Frei, Markus, CoLaus Cohort, Aubert, V., Barth, J., Battegay, M., Bernasconi, E., Böni, J., Bucher, H.C., Burton-Jeangros, C., Calmy, A., Egger, M., Elzi, L., Fehr, J., Fellay, J., Furrer, H., Fux, C.A., Gorgievski, M., Günthard, H., Haerry, D., Hasse, B., Hirsch, H.H., Hösli, I., Kahlert, C., Kaiser, L., Keiser, O., Klimkait, T., Kouyos, R., Kovari, H., Ledergerber, B., Martinetti, G., Martinez de Tejada, B., Metzner, K., Müller, N., Nadal, D., Pantaleo, G., Rauch, A., Regenass, S., Rickenbach, M., Rudin, C., Schöni-Affolter, F., Schmid, P., Schultze, D., Schüpbach, J., Speck, R., Staehelin, C., Tarr, P., Telenti, A., Trkola, A., Vernazza, P., Weber, R., Yerly, S., Jean-Michel, A., Murielle, B., Jean Michel, G., Christoph, H., Thomas, L., Pedro, M.V., Vincent, M., Fred, P., Martin, P., Peter, V., Roland, V.K., Aidacic, V., Gerard, W., Jürg, B., Markus, B., Heinz, B., Martin, B., Hans-Ulrich, B., Ivo, B., Reto, C., Isabelle, C., Corinne, C., Sima, D., Peter, D., Simone, E., Andrea, F., Markus, F., Claudius, F., Jakob, F., Ali, G.M., Matthias, G., Denis, H., Marcel, H., Walter, H., Simon, H., Felix, H., Paul, H., Eva, K., Vladimir, K., Daniel, K., Stephan, K., Beat, K., Benedict, K., Heidi, K., Vesna, L., Giovanni, L., Werner, L.H., Phillippe, L., Severin, L., Christoph, M., Jürgen, M., Damian, M., Werner, M., Titus, M., Valentina, N., Jakob, R., Thomas, R., Hana, S., Frank, S., Georg, S., Oliver, S., Pietro, S., Jacques, S., Alfred, S., Alois, S., Claudia, S., Othmar, S., Phuoc, T.T., Marco, V., Alessandro, V., René, V.A., Hans, W., Fritz, W., Johanna, W.S., Joseph, W., and Marco, Z.
Subjects: medicine.medical_specialty, multimorbidity, Population, 610 Medicine & health, Rate ratio, Major Articles, ddc:616.89, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, Medicine, 030212 general & internal medicine, Poisson regression, HIV-infection, education, ddc:613, ddc:616, 2. Zero hunger, 0303 health sciences, education.field_of_study, 030306 microbiology, business.industry, Incidence (epidemiology), virus diseases, medicine.disease, Comorbidity, Confidence interval, 3. Good health, comorbidity, Infectious Diseases, Oncology, Immunology, symbols, 570 Life sciences, biology, business, Body mass index, Cohort study
Abstract: AIDS-associated morbidity has diminished due to excellent viral control. Multimorbidity are more prevalent and incident in Swiss HIV-positive persons compared to HIV-negative controls. However, smoking, but not HIV status, had a strong impact on cardiovascular risk and multimorbidity., Background. Although acquired immune deficiency syndrome-associated morbidity has diminished due to excellent viral control, multimorbidity may be increasing among human immunodeficiency virus (HIV)-infected persons compared with the general population. Methods. We assessed the prevalence of comorbidities and multimorbidity in participants of the Swiss HIV Cohort Study (SHCS) compared with the population-based CoLaus study and the primary care-based FIRE (Family Medicine ICPC-Research using Electronic Medical Records) records. The incidence of the respective endpoints were assessed among SHCS and CoLaus participants. Poisson regression models were adjusted for age, sex, body mass index, and smoking. Results. Overall, 74 291 participants contributed data to prevalence analyses (3230 HIV-infected; 71 061 controls). In CoLaus, FIRE, and SHCS, multimorbidity was present among 26%, 13%, and 27% of participants. Compared with nonsmoking individuals from CoLaus, the incidence of cardiovascular disease was elevated among smoking individuals but independent of HIV status (HIV-negative smoking: incidence rate ratio [IRR] = 1.7, 95% confidence interval [CI] = 1.2–2.5; HIV-positive smoking: IRR = 1.7, 95% CI = 1.1–2.6; HIV-positive nonsmoking: IRR = 0.79, 95% CI = 0.44–1.4). Compared with nonsmoking HIV-negative persons, multivariable Poisson regression identified associations of HIV infection with hypertension (nonsmoking: IRR = 1.9, 95% CI = 1.5–2.4; smoking: IRR = 2.0, 95% CI = 1.6–2.4), kidney (nonsmoking: IRR = 2.7, 95% CI = 1.9–3.8; smoking: IRR = 2.6, 95% CI = 1.9–3.6), and liver disease (nonsmoking: IRR = 1.8, 95% CI = 1.4–2.4; smoking: IRR = 1.7, 95% CI = 1.4–2.2). No evidence was found for an association of HIV-infection or smoking with diabetes mellitus. Conclusions. Multimorbidity is more prevalent and incident in HIV-positive compared with HIV-negative individuals. Smoking, but not HIV status, has a strong impact on cardiovascular risk and multimorbidity.
Published: 2015

35. Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty

Author: Toos Van Beijsterveldt, Nicholas Schork, Ruth Loos, Eleftheria Zeggini, LAURA CRISPONI, Valur Emilsson, Nicole Soranzo, Ozren Polasek, Elisabeth Thiering, Elina Hypponen, Andrew Hattersley, Craig Pennell, Alexandra Lewin, ANGELO SCUTERI, Adamo Pio D'Adamo, Antje Körner, Peter Kraft, Thor Aspelund, Timo Lakka, Johannes Kettunen, Mara Marongiu, Christel Middeldorp, Mika Kähönen, Lachlan Coin, Alina Rodriguez, Terho Lehtimäki, Kalliope Panoutsopoulou, Carol Wang, Kathryn Lunetta, George Davey Smith, Debbie A Lawlor, Jianjun Liu, Nicholas Timpson, Xavier Estivill, Tuomas Kilpeläinen, Thomas Price, Mariona Bustamante, Evangelia Stergiakouli, Struan Grant, Gerard Waeber, Lyle John Palmer, Paolo Gasparini, Katja Pahkala, André Scherag, John Holloway, Carmen Iñiguez, Paul Elliott, Albert Vernon Smith, MANUELA UDA, Harri Niinikoski, Oliver Davis, Mads Melbye, Ida Surakka, Frank Geller, Rick Jansen, Mark McCarthy, Cecilia Lindgren, Hilleke Evertje Hulshoff Pol, Nicole Warrington, Ellen Demerath, ReproGen Consortium, Early Growth Genetics (EGG) Consortium, Cousminer, Diana L, Stergiakouli, Evangelia, Berry, Diane J, Ang, Wei, Hyppönen, Elina, Widen, Elisabeth, Biological Psychology, EMGO+ - Mental Health, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hebebrand, Johannes (Beitragende*r), Hinney, Anke (Beitragende*r), Psychiatry, and EMGO - Mental health
Subjects: Male, Netherlands Twin Register (NTR), puberty, Medizin, Body Mass Index, 0302 clinical medicine, Sexual maturity, Breast, Sexual Maturation, Child, Genetics (clinical), Adiposity, 2. Zero hunger, 0303 health sciences, Genome, Articles, General Medicine, Menarche, Female, medicine.medical_specialty, Adolescent, Genotype, males, 030209 endocrinology & metabolism, Genitalia, Male, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Sex Factors, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, medicine, Humans, Sex organ, Allele, Molecular Biology, Tanner scale, 030304 developmental biology, Breast development, maturation, ta1184, Puberty, ta3121, medicine.disease, Obesity, body mass, Endocrinology, Genetic Loci, Body mass index, Chromosomes, Human, Pair 16, Genome-Wide Association Study, Transcription Factors
Abstract: Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
Published: 2014

36. Swiss Medical Weekly: Quo vadis?

Author: Adriano Aguzzi and Gérard Waeber
Subjects: Medicine
Abstract: No abstract available
Published: 2022
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37. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts

Author: Benjamin Voight, Guillaume Pare, Ruth Loos, Michael Preuss, Åsa Johansson, Eco De Geus, Michael Weedon, Marjo-Riitta Jarvelin, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Nicole Glazer, Mattias Lorentzon, Braxton Mitchell, Nicole Soranzo, Patricia Munroe, Ozren Polasek, Elisabeth Thiering, Marika Kaakinen, Carla Vogel, Jennie Hui, Elina Hypponen, ROBERTO ELOSUA, Amanda Bennett, Michael Stumvoll, Andrew Hattersley, Peter P Pramstaller, Lambertus Kiemeney, Sophie Visvikis-Siest, Vilmundur Gudnason, John Whittaker, Aroon Hingorani, Thor Aspelund, Dale Nyholt, Mary Feitosa, Vimal Karani, Mika Kähönen, Lachlan Coin, Malcolm Dunlop, Josee Dupuis, Terho Lehtimäki, Peter Visscher, Katja Aben, Daniel Witte, Cyrus Cooper, Stefan Pilz, Willem Ouwehand, Eleanor Wheeler, Peter Kovacs, Debbie A Lawlor, Kevin Jacobs, Evropi Theodoratou, Hana Lango Allen, Rosanda Mulic, Rui Li, Stephen Kritchevsky, Philippe Froguel, Soumya Raychaudhuri, Cornelia Van Duijn, Andrew Wood, Chiara Lanzani, Tonu Esko, Sadaf Farooqi, Reedik Mägi, Gerard Waeber, Claes Ohlsson, André Scherag, Marcus Kleber, Thomas Meitinger, Lina Zgaga, Denise Houston, Karl Michaëlsson, Robert Weyant, Thomas Wang, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Gonneke Willemsen, Mark McCarthy, Cecilia Lindgren, Olle Melander, Igor Rudan, Maris Teder-Laving, Liesbeth Vandenput, Vimaleswaran, K, Berry, Dj, Lu, C, Tikkanen, E, Pilz, S, Hiraki, Lt, Cooper, Jd, Dastani, Z, Li, R, Houston, Dk, Wood, Ar, Michaëlsson, K, Vandenput, L, Zgaga, L, YERGES ARMSTRONG, Lm, Mccarthy, Mi, Dupuis, J, Kaakinen, M, Kleber, Me, Jameson, K, Arden, N, Raitakari, O, Viikari, J, Lohman, Kk, Ferrucci, L, Melhus, H, Ingelsson, E, Byberg, L, Lind, L, Lorentzon, M, Salomaa, V, Campbell, H, Dunlop, M, Mitchell, Bd, Herzig, Kh, Pouta, A, Hartikainen, Al, Manunta, Paolo, Streeten, Ea, Theodoratou, E, Jula, A, Wareham, Nj, Ohlsson, C, Frayling, Tm, Kritchevsky, Sb, Spector, Td, Richards, Jb, Lehtimäki, T, Ouwehand, Wh, Kraft, P, Cooper, C, März, W, Power, C, Loos, Rj, Wang, Tj, Järvelin, Mr, Whittaker, Jc, Hingorani, Ad, Hyppönen, E., Council, Medical Research, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Vimaleswaran, Karani S, Berry, Diane J, Lu, Chen, Tikkanen, Emmi, Hyppönen, Elina, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, Hinney, Anke (Beitragende*r), Scherag, Susann (Beitragende*r), Hebebrand, Johannes (Beitragende*r), Epidemiology and Data Science, Psychiatry, EMGO - Lifestyle, overweight and diabetes, Genetic Investigation of Anthropometric Traits-GIANT Consortium, Speliotes, E.K., Willer, C.J., Berndt, S.I., Monda, K.L., Thorleifsson, G., Jackson, A.U., Allen, H.L., Lindgren, C.M., Jian'an, L., Mägi, R., Randall, J.C., Vedantam, S., Winkler, T.W., Qi, L., Workalemahu, T., Heid, I.M., Steinthorsdottir, V., Stringham, H.M., Weedon, M.N., Wheeler, E., Wood, A.R., Ferreira, T., Weyant, R.J., Segrè, A.V., Estrada, K., Liang, L., Nemesh, J., Park, J.H., Gustafsson, S., Kilpeläinen, T.O., Yang, J., Bouatia-Naji, N., Tõnu, E., Feitosa, M.F., Kutalik, Z., Mangino, M., Raychaudhuri, S., Scherag, A., Smith, A.V., Welch, R., Zhao, J.H., Aben, K.K., Absher, D.M., Amin, N., Dixon, A.L., Fisher, E., Glazer, N.L., Goddard, M.E., Heard-Costa, N.L., Hoesel, V., Hottenga, J.J., Johansson, Å., Johnson, T., Ketkar, S., Lamina, C., Li, S., Moffatt, M.F., Myers, R.H., Narisu, N., Perry, J.R., Peters, M.J., Preuss, M., Ripatti, S., Rivadeneira, F., Sandholt, C., Scott, L.J., Timpson, N.J., Tyrer, J.P., van Wingerden, S., Watanabe, R.M., White, C.C., Wiklund, F., Barlassina, C., Chasman, D.I., Cooper, M.N., Jansson, J.O., Lawrence, R.W., Pellikka, N., Prokopenko, I., Shi, J., Thiering, E., Alavere, H., Alibrandi, M.T., Almgren, P., Arnold, A.M., Aspelund, T., Atwood, L.D., Balkau, B., Balmforth, A.J., Bennett, A.J., Ben-Shlomo, Y., Bergman, R.N., Bergmann, S., Biebermann, H., Blakemore, A.I., Boes, T., Bonnycastle, L.L., Bornstein, S.R., Brown, M.J., Buchanan, T.A., Busonero, F., Campbell, H., Cappuccio, F.P., Cavalcanti-Proença, C., Chen, Y.D., Chen, C.M., Chines, P.S., Clarke, R., Coin, L., Connell, J., Day, I.N., Heijer, M., Duan, J., Ebrahim, S., Elliott, P., Elosua, R., Eiriksdottir, G., Erdos, M.R., Eriksson, J.G., Facheris, M.F., Felix, S.B., Fischer-Posovszky, P., Folsom, A.R., Friedrich, N., Freimer, N.B., Fu, M., Gaget, S., Gejman, P.V., Geus, E.J., Gieger, C., Gjesing, A.P., Goel, A., Goyette, P., Grallert, H., Gräßler, J., Greenawalt, D.M., Groves, C.J., Gudnason, V., Guiducci, C., Hartikainen, A.L., Hassanali, N., Hall, A.S., Havulinna, A.S., Hayward, C., Heath, A.C., Hengstenberg, C., Hicks, A.A., Hinney, A., Hofman, A., Homuth, G., Hui, J., Igl, W., Iribarren, C., Isomaa, B., Jacobs, K.B., Jarick, I., Jewell, E., John, U., Jørgensen, T., Jousilahti, P., Jula, A., Kaakinen, M., Kajantie, E., Kaplan, L.M., Kathiresan, S., Kettunen, J., Kinnunen, L., Knowles, J.W., Kolcic, I., König, I.R., Koskinen, S., Kovacs, P., Kuusisto, J., Kraft, P., Kvaløy, K., Laitinen, J., Lantieri, O., Lanzani, C., Launer, L.J., Lecoeur, C., Lehtimäki, T., Lettre, G., Liu, J., Lokki, M.L., Lorentzon, M., Luben, R.N., Ludwig, B., Manunta, P., Marek, D., Marre, M., Martin, N.G., McArdle, W.L., McCarthy, A., McKnight, B., Meitinger, T., Melander, O., Meyre, D., Midthjell, K., Montgomery, G.W., Morken, M.A., Morris, A.P., Mulic, R., Ngwa, J.S., Nelis, M., Neville, M.J., Nyholt, D.R., O'Donnell, C.J., O'Rahilly, S., Ong, K.K., Oostra, B., Paré, G., Parker, A.N., Perola, M., Pichler, I., Pietiläinen, K.H., Platou, C.G., Polasek, O., Pouta, A., Rafelt, S., Raitakari, O., Rayner, N.W., Ridderstråle, M., Rief, W., Ruokonen, A., Robertson, N.R., Rzehak, P., Salomaa, V., Sanders, A.R., Sandhu, M.S., Sanna, S., Saramies, J., Savolainen, M.J., Scherag, S., Schipf, S., Schreiber, S., Schunkert, H., Silander, K., Sinisalo, J., Siscovick, D.S., Smit, J.H., Soranzo, N., Sovio, U., Stephens, J., Surakka, I., Swift, AJ., Tammesoo, M.L., Tardif, J.C., Teder-Laving, M., Teslovich, T.M., Thompson, J.R., Thomson, B., Tönjes, A., Tuomi, T., van Meurs, J.B., van Ommen, G.J., Vatin, V., Viikari, J., Visvikis-Siest, S., Vitart, V., Vogel, C.I., Voight, B.F., Waite, L.L., Wallaschofski, H., Walters, G.B., Widen, E., Wiegand, S., Wild, S.H., Willemsen, G., Witte, D.R., Witteman, J.C., Xu, J., Zhang, Q., Zgaga, L., Ziegler, A., Zitting, P., Beilby, J.P., Farooqi, I.S., Hebebrand, J., Huikuri, H.V., James, AL., Kähönen, M., Levinson, D.F., Macciardi, F., Nieminen, M.S., Ohlsson, C., Palmer, L.J., Ridker, P.M., Stumvoll, M., Beckmann, J.S., Boeing, H., Boerwinkle, E., Boomsma, D.I., Caulfield, M.J., Chanock, S.J., Collins, F.S., Cupples, L.A., Smith, G.D., Erdmann, J., Froguel, P., Grönberg, H., Gyllensten, U., Hall, P., Hansen, T., Harris, T.B., Hattersley, A.T., Hayes, R.B., Heinrich, J., Hu, F.B., Hveem, K., Illig, T., Jarvelin, M.R., Kaprio, J., Karpe, F., Khaw, K.T., Kiemeney, L.A., Krude, H., Laakso, M., Lawlor, D.A., Metspalu, A., Munroe, P.B., Ouwehand, W.H., Pedersen, O., Penninx, B.W., Peters, A., Pramstaller, P.P., Quertermous, T., Reinehr, T., Rissanen, A., Rudan, I., Samani, N.J., Schwarz, P.E., Shuldiner, A.R., Spector, T.D., Tuomilehto, J., Uda, M., Uitterlinden, A., Valle, T.T., Wabitsch, M., Waeber, G., Wareham, N.J., Watkins, H., Wilson, J.F., Wright, A.F., Zillikens, M.C., Chatterjee, N., McCarroll, S.A., Purcell, S., Schadt, E.E., Visscher, P.M., Assimes, T.L., Borecki, I.B., Deloukas, P., Fox, C.S., Groop, L.C., Haritunians, T., Hunter, D.J., Kaplan, R.C., Mohlke, K.L., O'Connell, J.R., Peltonen, L., Schlessinger, D., Strachan, D.P., van Duijn, C.M., Wichmann, H.E., Frayling, T.M., Thorsteinsdottir, U., Abecasis, G.R., Barroso, I., Boehnke, M., Stefansson, K., North, K.E., McCarthy, M.I., Hirschhorn, J.N., Ingelsson, E., Loos, R.J., Medical Research Council (MRC), and National Institute for Health Research
Subjects: Male, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, obesity, 25-HYDROXYVITAMIN D, D INSUFFICIENCY, Epidemiology, Medizin, vitamin D, Aetiology, screening and detection [ONCOL 5], Medical and Health Sciences, Gastroenterology, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, Medicine, 030212 general & internal medicine, Vitamin D, 2. Zero hunger, Genetics, Aged, 80 and over, Evidence-Based Medicine, Confounding, 11 Medical And Health Sciences, General Medicine, Middle Aged, 3. Good health, PREVALENCE, Europe, Phenotype, Genetic Epidemiology, Biological Markers, Female, Life Sciences & Biomedicine, Research Article, Vitamin, Adult, medicine.medical_specialty, vitamin D deficiency, genetic variants, Genetic Investigation of Anthropometric Traits-GIANT Consortium, European Continental Ancestry Group, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, body mass index, Polymorphism, Single Nucleotide, Risk Assessment, White People, COMMON OBESITY, 03 medical and health sciences, D DEFICIENCY, Medicine, General & Internal, SDG 3 - Good Health and Well-being, General & Internal Medicine, Internal medicine, Mendelian randomization, Vitamin D and neurology, INSTRUMENTAL VARIABLES, Humans, Genetic Predisposition to Disease, Obesity, GENOME-WIDE ASSOCIATION, Biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, Science & Technology, Population Biology, business.industry, CARDIOVASCULAR-DISEASE RISK, ta3121, Mendelian Randomization Analysis, medicine.disease, Vitamin D Deficiency, BODY-MASS INDEX, chemistry, Genetic epidemiology, 3121 General medicine, internal medicine and other clinical medicine, Multivariate Analysis, North America, Genetic Polymorphism, Linear Models, business, Body mass index, Population Genetics, Biomarkers
Abstract: A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity., Background Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). Conclusions On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. Please see later in the article for the Editors' Summary, Editors' Summary Background Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements. Why Was This Study Done? Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations. What Did the Researchers Do and Find? The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium. What Do These Findings Mean? These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001383. The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population The World Health Organization provides information on obesity (in several languages) The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D The International Obesity Taskforce provides information about the global obesity epidemic The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish) The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish) MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish) Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits
Published: 2013

38. Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor

Author: Gerard Waeber
Subjects: Endocrinology, General Medicine, Molecular Biology
Published: 1996

39. Association between Mediterranean Diet and Type 2 Diabetes: Multiple Cross-Sectional Analyses

Author: Adèle Bossel, Gérard Waeber, Antoine Garnier, Pedro Marques-Vidal, and Vanessa Kraege
Subjects: Mediterranean diet, type 2 diabetes, nutrition, non communicable diseases, diet score, adherence, Nutrition. Foods and food supply, TX341-641
Abstract: Aim: To assess whether the Mediterranean diet (MD) is associated with lower levels of type 2 diabetes (T2D) in a non-Mediterranean population. Methods: Cross-sectional analysis of follow-ups 1 (FU1, 2009–2012, n = 4398, 45.7% men, 57.7 ± 10.5 years), 2 (FU2, 2014–2017, n = 3154, 45.0% men, 61.7 ± 9.9 years), and 3 (FU3, 2018–2021, n = 2394, 45.2% men, 65.0 ± 9.6 years) of the Colaus|PsyCoLaus study (Lausanne, Switzerland). Two MD scores (Trichopoulou, noted MD1, and Sofi, noted MD2) were calculated using participants’ dietary data. T2D was defined as a fasting plasma glucose ≥7 mmol/L and/or the presence of an antidiabetic drug treatment. Results: Participants with the highest MD adherence had a higher educational level, a lower BMI, were less frequent smokers, presented less frequently with hypertension, and were more frequent alcohol consumers. After multivariable adjustment, no differences were found between participants with and without T2D regarding MD scores: 3.93 ± 0.07 vs. 3.97 ± 0.02; 4.08 ± 0.10 vs. 3.98 ± 0.03, and 3.83 ± 0.11 vs. 3.97 ± 0.03, respectively, for the MD1 score in FU1, FU2, and FU3. In addition, no association was found between adherence to MD and T2D: odds ratio (and 95% confidence interval) for medium and high relative to low adherence to MD1: 0.87 (0.68–1.10) and 0.89 (0.64–1.24) in FU1, 1.04 (0.76–1.42) and 1.07 (0.68–1.67) in FU2, and 0.73 (0.53–1.03) and 0.61 (0.37–1.02) in FU3, respectively. Corresponding results for MD2 were 0.90 (0.70–1.15) and 1.03 (0.69–1.53) in FU1, 1.16 (0.82–1.63) and 1.40 (0.81–2.41) in FU2, and 0.93 (0.65–1.34) and 0.55 (0.28–1.08) in FU3. Conclusion: We found no association between Mediterranean diet adherence and T2D in a non-Mediterranean population.
Published: 2023
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40. No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels

Author: Daniel R. Witte, Han Chen, Lori L. Bonnycastle, Mette Aadahl, Olga D. Carlson, Josée Dupuis, Yii-Der Ida Chen, Tanya M. Teslovich, Richard M. Watanabe, Frida Renström, John W. Holloway, Meena Kumari, Michael Boehnke, Audrey Y. Chu, Robert A. Scott, Alisa K. Manning, Ajay Yesupriya, Anke Tönjes, Niels Grarup, Ingegerd Johansson, Nita G. Forouhi, Inês Barroso, Aroon D. Hingorani, Dmitry Shungin, Mika Kivimäki, Weijia Xie, David Couper, Diana Marek, Peter Schwarz, Torben Hansen, Jose C. Florez, Camilla H. Sandholt, Philippe Froguel, Leif Groop, Vasiliki Lagou, Johanna Kuusisto, W. H. Linda Kao, Suzannah Bumpstead, Nabila Bouatia-Naji, Inga Prokopenko, Peter Kovacs, Zoltán Kutalik, Eric Boerwinkle, Kenneth Rice, Michael R. Erdos, Gabriele Müller, Claire Levy-Marchal, Alena Stančáková, Jürgen Grässler, Erik Ingelsson, Mario A. Morken, Gerard Waeber, Eric J. Brunner, Ulf Ekelund, Luigi Ferrucci, Francis S. Collins, Mark Walker, Laura J. Rasmussen-Torvik, Markku Laakso, Stefan Gustafsson, Stefan R. Bornstein, Guo Li, Dan E. Arking, Torben Jørgensen, Peter Vollenweider, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Oluf Pedersen, Avan Aihie Sayer, Heather M. Stringham, Bruce M. Psaty, Claudia Langenberg, Soren Brage, Ruth J. F. Loos, David S. Siscovick, Denis Rybin, Gordon H. Williams, Caroline S. Fox, Sven Bergmann, Felicity Payne, James B. Meigs, Marie-France Hivert, Nicole L. Glazer, Jerome I. Rotter, Elaine M. Dennison, Andrew R. Wood, Göran Hallmans, Nicole F. Dowling, Peter S. Chines, Cyrus Cooper, Josephine S. Egan, Paul W. Franks, Frank B. Hu, Michael Marmot, Pedro Marques-Vidal, Kari E. North, James S. Pankow, Valeri Lyssenko, Cécile Lecoeur, Toshiko Tanaka, Daniel R. Barnes, Nicholas J. Wareham, Anna Jonsson, Bo Isomaa, Anne U. Jackson, Karen A. Jameson, Barnes, Daniel [0000-0002-3781-7570], Brage, Soren [0000-0002-1265-7355], Forouhi, Nita [0000-0002-5041-248X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)
Subjects: Blood Glucose, medicine.medical_specialty, DIABETES PREVENTION PROGRAM, ENDOCRINOLOGY & METABOLISM, Genotype, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Physical exercise, Single-nucleotide polymorphism, PROGRESSION, Type 2 diabetes, Biology, Motor Activity, Polymorphism, Single Nucleotide, Body Mass Index, Epigenesis, Genetic, 03 medical and health sciences, TYPE-2, MELLITUS, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Allele, Life Style, POLYMORPHISMS, 030304 developmental biology, Genetic association, RISK, 0303 health sciences, ENVIRONMENT, Science & Technology, COMMON VARIANTS, Genetics/Genomes/Proteomics/Metabolomics, 11 Medical And Health Sciences, medicine.disease, Endocrinology, Gene Expression Regulation, LIFE-STYLE INTERVENTION, Body mass index, Life Sciences & Biomedicine, TRAITS
Abstract: Gene–lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13–0.31], P = 1.63 × 10−6). All SNPs were associated with 2-h glucose (β = 0.06–0.12 mmol/allele, P ≤ 1.53 × 10−7), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene–lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
Published: 2012

41. [Hypoglycemia in patients treated with an external insulin pump]

Author: Jean-Christophe, Laurent, Gerard, Waeber, Juan, Ruiz, and Pierre-Nicolas, Carron
Subjects: Insulin Infusion Systems, Diabetes Mellitus, Humans, Hypoglycemic Agents, Insulin, Hypoglycemia
Abstract: Hypoglycemia is a potentially serious complication of insulin therapy. Some insulin-dependent diabetic patients can benefit from continuous subcutaneous insulin infusion therapy (an "insulin pump"), which in most case improves glycemia control and decreases the occurrence of hypoglycemic episodes. However, such events may occur, particularly during initial treatment phases or pregnancy. Severe hypoglycemia is mainly managed by stopping the insulin pump and insuring an adequate carbohydrate intake. Patients with insulin pumps and their entourage should receive specific instruction in the adjustment of pump flow in the presence of dysglycemia-inducing circumstances (illness, physical exertion), as well as in anticipation of high-risk situations, such as motor-vehicle driving.
Published: 2011

42. Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

Author: Benjamin Voight, Amelie Bonnefond, Mark Caulfield, Guillaume Pare, Manal Abdelmalek, Eleftheria Zeggini, Jeffrey Schwimmer, Anna Gloyn, Michael Preuss, Åsa Johansson, LAURA CRISPONI, Eco De Geus, Michael Weedon, Jeanne Clark, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Nicole Glazer, Jaakko Kaprio, Alan Shuldiner, Braxton Mitchell, Patricia Munroe, Ozren Polasek, Elisabeth Thiering, Carla Vogel, Jennie Hui, ROBERTO ELOSUA, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Alexander Doney, Peter P Pramstaller, Christian Dina, Lambertus Kiemeney, Sophie Visvikis-Siest, ANGELO SCUTERI, Udo Seedorf, Vilmundur Gudnason, Peter Kraft, Aroon Hingorani, Michael Marmot, Dale Nyholt, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Mika Kähönen, David Hillman, Lachlan Coin, Eric Brunner, Terho Lehtimäki, Man Li, John Beilby, Peter Visscher, Anette P Gjesing, James Pankow, Ruben Hernaez, Taina Lajunen, Katja Aben, Daniel Witte, Willem Ouwehand, Eleanor Wheeler, Peter Kovacs, Debbie A Lawlor, Kevin Jacobs, Jianjun Liu, Joseph Massaro, Hana Lango Allen, Inga Prokopenko, Rafn Benediktsson, Philippe Froguel, Soumya Raychaudhuri, Cornelia Van Duijn, Annette Peters, Nita Forouhi, Chiara Lanzani, Tonu Esko, Ko Willems van Dijk, Sadaf Farooqi, John Carr, Reedik Mägi, David Melzer, Gerard Waeber, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, Claes Ohlsson, Perry Elliott, André Scherag, Inke König, Stephen O'rahilly, Thomas Meitinger, Michael Goddard, Lina Zgaga, Robert Weyant, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Avan Aihie Sayer, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Olle Melander, Igor Rudan, Maris Teder-Laving, Hugh Watkins, Ulrich John, Epidemiology, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C. I. (Beitragende*r), Hebebrand, Johannes (Beitragende*r), Functional Genomics, Biological Psychology, Neuroscience Campus Amsterdam - integrative Analysis & Modeling, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, McCarthy, Mark I, Apollo - University of Cambridge Repository, Medical Research Council (MRC), Speliotes, Ek, YERGES ARMSTRONG, Lm, Wu, J, Hernaez, R, Kim, Lj, Palmer, Cd, Gudnason, V, Eiriksdottir, G, Garcia, Me, Launer, Lj, Nalls, Ma, Clark, Jm, Mitchell, Bd, Shuldiner, Ar, Butler, Jl, Tomas, M, Hoffmann, U, Hwang, Sj, Massaro, Jm, O'Donnell, Cj, Sahani, Dv, Salomaa, V, Schadt, Ee, Schwartz, Sm, Siscovick, D, Nash, Crn, Manunta, Paolo, Giant, Consortium, Magic, Investigator, Voight, Bf, Carr, Jj, Feitosa, Mf, Harris, Tb, Fox, C, Smith, Av, Kao, Wh, Hirschhorn, Jn, Borecki, Ib, Gold, Consortium, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Genetic Epidemiology, O', Donnell, Cj, Giant, and Paolisso, Giuseppe
Subjects: Blood Glucose, Male, Netherlands Twin Register (NTR), Cancer Research, Medizin, Genome-wide association study, Hepatitis, Diabetes and Endocrinology/Obesity, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Lectins, Nonalcoholic fatty liver disease, 80 and over, Insulin, 2.1 Biological and endogenous factors, Aetiology, Tomography, Adaptor Proteins, Signal Transducing/genetics Adult Aged Aged, 80 and over Blood Glucose/analysis Case-Control Studies Chondroitin Sulfate Proteoglycans/genetics Cohort Studies Fatty Liver/*genetics/metabolism/radiography Genome-Wide Association Study Humans Insulin/blood Lectins, C-Type/genetics Lipase/genetics Male Membrane Proteins/genetics Middle Aged Mutation, Missense Nerve Tissue Proteins/genetics Polymorphism, Single Nucleotide Quantitative Trait Loci Tomography, X-Ray Computed, Genetics (clinical), Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Framingham Risk Score, C-Type, Liver Disease, Fatty liver, Adaptor Proteins, Single Nucleotide, Middle Aged, X-Ray Computed, 3. Good health, GOLD Consortium, 030211 gastroenterology & hepatology, Research Article, Adult, lcsh:QH426-470, Quantitative Trait Loci, Chronic Liver Disease and Cirrhosis, Mutation, Missense, genome-wide, fatty liver, metabolic, Nerve Tissue Proteins, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, Gastroenterology and Hepatology/Hepatology, MAGIC Investigators, 03 medical and health sciences, Clinical Research, GIANT Consortium, medicine, Humans, Lectins, C-Type, Adiponutrin, NASH CRN, ddc:610, Polymorphism, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Adaptor Proteins, Signal Transducing, Aged, 030304 developmental biology, 0604 Genetics, Genetic heterogeneity, Prevention, Human Genome, Signal Transducing, Membrane Proteins, Lipase, medicine.disease, 3141 Health care science, Fatty Liver, lcsh:Genetics, Chondroitin Sulfate Proteoglycans, Case-Control Studies, Mutation, Missense, Steatosis, Steatohepatitis, Tomography, X-Ray Computed, Digestive Diseases, Neurocan, Genome-Wide Association Study, Developmental Biology
Abstract: Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p, Author Summary NAFLD is a spectrum of disease that ranges from steatosis to steatohepatitis (nonalcoholic steatohepatitis or NASH: inflammation around the fat) to fibrosis/cirrhosis. Hepatic steatosis can be measured non-invasively using computed tomography (CT) whereas NASH/fibrosis is assessed histologically. The genetic underpinnings of NAFLD remain to be determined. Here we estimate that 26%–27% of the variation in CT measured hepatic steatosis is heritable or genetic. We identify three variants near PNPLAL3, NCAN, and PPP1R3B that associate with CT hepatic steatosis and show that variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B, associate with histologic lobular inflammation/fibrosis. Variants in or near NCAN, GCKR, and PPP1R3B associate with altered serum lipid levels, whereas those in or near LYPLAL1 and PNPLA3 do not. Variants near GCKR and PPP1R3B also affect glycemic traits. Thus, we show that NAFLD is genetically influenced and expand the number of common genetic variants that associate with this trait. Our findings suggest that development of hepatic steatosis, NASH/fibrosis, or abnormalities in metabolic traits are probably influenced by different metabolic pathways that may represent distinct therapeutic targets.
Published: 2011

43. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

Author: Benjamin Voight, Amelie Bonnefond, Mark Caulfield, Jong-Young Lee, Ruth Loos, Nancy Heard-Costa, Eleftheria Zeggini, Cristiano FAVA, Anna Gloyn, Michael Preuss, Åsa Johansson, LAURA CRISPONI, Eco De Geus, Michael Weedon, Jeanne Clark, Francesco CUCCA, Marjo-Riitta Jarvelin, Torben Jørgensen, Andrea Maschio, Kirsi Pietiläinen, Nicole Glazer, Jaakko Kaprio, Valur Emilsson, Goncalo Abecasis, Andrew Taylor, Nicole Soranzo, Serena Sanna, Patricia Munroe, Ozren Polasek, Jan A. Staessen, Jennie Hui, Elina Hypponen, ROBERTO ELOSUA, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Bruce H.R. Wolffenbuttel, Alexander Doney, Peter P Pramstaller, Christian Dina, Lambertus Kiemeney, Sophie Visvikis-Siest, Mohammad Arfan Ikram, ANGELO SCUTERI, Udo Seedorf, Behrooz Ziad Alizadeh, John Whitfield, Vilmundur Gudnason, Maris Laan, Chris Wallace, Gavin Lucas, E Shyong Tai, Peter Kraft, Michael Marmot, Thor Aspelund, Dale Nyholt, Christian Gieger, Mika Kivimaki, Michael Sternberg, Lorena Citterio, Weiguo Zhang, Mary Feitosa, María Soler Artigas, Claudia Langenberg, Mika Ala-Korpela, Stavroula Kanoni, Uwe Völker, Mika Kähönen, Tomonori Okamura, Marcus Dörr, David Hillman, Lachlan Coin, Gideon Hirschfield, Eric Brunner, Maryam Kavousi, Terho Lehtimäki, Man Li, Carsten Oliver Schmidt, John Beilby, Peter Visscher, Sally Ricketts, Katja Aben, Halit Ongen, Christie Ballantyne, Adebowale Adeyemo, Fabio Marroni, Willem Ouwehand, Toby Johnson, Meena Kumari, Peter Kovacs, Debbie A Lawlor, Jianjun Liu, Grant Montgomery, Nicholas Martin, Francesco Mattace-Raso, Inga Prokopenko, Rafn Benediktsson, Margus Viigimaa, Peter Würtz, Philippe Froguel, Fadi Charchar, Soumya Raychaudhuri, Wolfram Goessling, Alena Yaluri, Cornelia Van Duijn, Timothy Frayling, Daniel Shriner, Nita Forouhi, Jana Van Vliet-Ostaptchouk, Bram Prins, Peter Whincup, David MASSON, Ronald Stolk, Ayse Demirkan, Janoš Terzić, James Pirruccello, Maciej Tomaszewski, Martin Tobin, Ko Willems van Dijk, John Carr, Elin Org, Reedik Mägi, Xiaofeng Zhu, Gerard Waeber, Koichi Matsuda, Winston Hide, Lyle John Palmer, Francois Pattou, Dorairaj Prabhakaran, Markus M. Lerch, Mark Wass, Claes Ohlsson, Paul O'Reilly, Vasiliki Lagou, Pedro Marques-Vidal, Sudha Seshadri, Tom Gaunt, Peter Wurz, Giriraj Ratan Chandak, Louise Wain, Antti Kangas, Matthijs Boekholdt, Niels Grarup, Jemma Hopewell, Thomas Meitinger, Lina Zgaga, Dag Steinar Thelle, Robert Weyant, Thomas Wang, Paul Elliott, Robert Luben, Albert Vernon Smith, Vinod Kumar, Pankaj Arora, MANUELA UDA, Daniel Gudbjartsson, Avan Aihie Sayer, Christa Meisinger, Kirsten Ohm Kyvik, Ming-Huei Chen, Susana Eyheramendy, Kenechi Ejebe, Stephen E Humphries, Ioanna Tzoulaki, Florian Kronenberg, Richard Bergman, Laura Zagato, Carlo Rivolta, NILUFER RAHMIOGLU, Vasan Ramachandran, Anna Dominiczak, Gonneke Willemsen, Mark McCarthy, Cecilia Lindgren, Olle Melander, Igor Rudan, Xueling Sim, Hugh Watkins, Edward Lakatta, Other departments, Experimental Vascular Medicine, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Chambers, John C, Zhang, Weihua, Sehmi, Joban, Li, Xiunzhong, Hypponen, Elina, Kooner, Jaspal S, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Faculteit Medische Wetenschappen/UMCG, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Psychiatry, NCA - Anxiety & Depression, NCA - Attention & Cognition, EMGO - Mental health, Epidemiology, Surgery, Gastroenterology & Hepatology, Pediatrics, Internal Medicine, and Ehret, Georg Benedikt
Subjects: Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Liver disease, Delta-5 Fatty Acid Desaturase, 0302 clinical medicine, HEPATOCELLULAR-CARCINOMA, GENETIC-VARIANTS, METABOLIC SYNDROME, ddc:616, Genetics, 0303 health sciences, Glycobiology, GWAS, liver enzymes, COMMON VARIANTS, Genomics, Single Nucleotide, C-REACTIVE PROTEIN, Enzymes, 3. Good health, GWAS liver enzymes plasma, Blood, Liver, 030220 oncology & carcinogenesis, HEREDITARY CHOLESTASIS, SUSCEPTIBILITY LOCI, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Enzymes/blood/genetics, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, CORONARY-HEART-DISEASE, Polymorphism, Gene, 030304 developmental biology, Hormonal regulation [IGMD 6], Liver/enzymology, Lipid metabolism, medicine.disease, SALT EXPORT PUMP, RISK-FACTORS, Genome-Wide Association Study, Liver function
Abstract: Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. Major support for the work came from European Commission (FP5, FP6 and FP7); European Science Foundation; European Science Council
Published: 2011

44. The promoter of the gene encoding 3',5'-cyclic adenosine monophosphate (cAMP) response element binding protein contains cAMP response elements: evidence for positive autoregulation of gene transcription

Author: Gerard Waeber, W Beckmann, Joel F. Habener, Terry E. Meyer, and Julia C. Lin
Subjects: Transcription, Genetic, p300-CBP coactivator family, Recombinant Fusion Proteins, Molecular Sequence Data, Response element, CREB, ATF/CREB, Endocrinology, Pregnancy, Cyclic AMP, Tumor Cells, Cultured, Humans, Amino Acid Sequence, Choriocarcinoma, RNA, Neoplasm, Cloning, Molecular, Protein kinase A signaling, Cyclic AMP Response Element-Binding Protein, Luciferases, Promoter Regions, Genetic, Enhancer, Cell Nucleus, Base Sequence, biology, Nuclear Proteins, Promoter, DNA, Exons, Molecular biology, Gene Expression Regulation, Neoplastic, Oligodeoxyribonucleotides, Protein Biosynthesis, Uterine Neoplasms, biology.protein, Female, CREB1, Protein Kinases
Abstract: The transcriptional transactivational activities of the phosphoprotein cAMP-response element-binding protein (CREB) are activated by the cAMP-dependent protein kinase A signaling pathway. Dimers of CREB bind to the palindromic DNA element 5'-TGACGTCA-3' (or similar motifs) called cAMP-responsive enhancers (CREs) found in the control regions of many genes, and activate transcription in response to phosphorylation of CREB by protein kinase A. Earlier we reported on the cyclical expression of the CREB gene in the Sertoli cells of the rat testis that occurred concomitant with the FSH-induced rise in cellular cAMP levels and suggested that transcription of the CREB gene may be autoregulated by cAMP-dependent transcriptional proteins. We now report the structure of the 5'-flanking sequence of the human CREB gene containing promoter activity. The promoter has a high content of guanosines and cytosines and lacks canonical TATA and CCAAT boxes typically found in the promoters of genes in eukaryotes. Notably, the promoter contains three CREs and transcriptional activities of a promoter-luciferase reporter plasmid transfected to placental JEG-3 cells are increased 3- to 5-fold over basal activities in response to either cAMP or 12-O-tetradecanoyl phorbol-14-acetate, and give 6- to 7-fold responses when both agents are added. The CREs bind recombinant CREB and endogenous CREB or CREB-like proteins contained in placental JEG-3 cells and also confer cAMP-inducible transcriptional activation to a heterologous minimal promoter. Our studies suggest that the expression of the CREB gene is positively autoregulated in trans.
Published: 1993

45. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Author: Fredrik Karpe, Ivonne Jarick, Julius S. Ngwa, Alan F. Wright, Robert Luben, Aaron R. Folsom, Sailaja Vedantam, Veikko Salomaa, Markku J. Savolainen, Robert Clarke, Shah Ebrahim, Thomas A. Buchanan, Mao Fu, Albert Hofman, Philippe Goyette, Camilla H. Sandholt, Fabio Macciardi, Elizabeth K. Speliotes, Barbara McKnight, Anne McCarthy, Mika Kaehoenen, Christian Gieger, Jorma S. A. Viikari, Nicholas J. Timpson, Kirsti Kvaløy, Douglas F. Levinson, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Andrew A. Hicks, Niina Pellikka, Charles C. White, Leena Peltonen, Reedik Maegi, John-Olov Jansson, Qunyuan Zhang, Claudia Lamina, Robert C. Kaplan, Peter M. Visscher, Laura J. Scott, Claes Ohlsson, Brian Thomson, Jubao Duan, Heikki V. Huikuri, Stephen O'Rahilly, Anette P. Gjesing, David P. Strachan, Caroline S. Fox, Sekar Kathiresan, Anna-Liisa Hartikainen, Johannes Kettunen, Maris Teder-Laving, Erik Ingelsson, Mario A. Morken, Peter Kovacs, Elisabeth Widen, Caroline Hayward, Eleanor Wheeler, Jing Hua Zhao, Vilmundur Gudnason, Panos Deloukas, Jacqueline C. M. Witteman, Gert-Jan B. van Ommen, Eric Boerwinkle, Martin Wabitsch, Christian Hengstenberg, Beverley Balkau, Thor Aspelund, Neelam Hassanali, Paul M. Ridker, Nicole L. Glazer, Joyce B. J. van Meurs, Michel Marre, Alan James, Ben A. Oostra, David Meyre, Ida Surakka, Stefan Schreiber, Nigel W. Rayner, Heribert Schunkert, Thomas Quertermous, Stefan Gustafsson, Peter Kraft, Benjamin F. Voight, Irene Pichler, Olle Melander, Ozren Polasek, Antti Jula, Alan R. Sanders, Andrew R. Wood, Yoav Ben-Shlomo, Thomas Illig, Jianjun Liu, Gerard Waeber, André G. Uitterlinden, Torben Hansen, Helene Alavere, André Scherag, Paolo Manunta, Johannes Hebebrand, Themistocles L. Assimes, Stefan R. Bornstein, Jaakko Tuomilehto, Morris Brown, Jianfeng Xu, Yii-Der Ida Chen, Nancy L. Heard-Costa, Cristen J. Willer, Henrik Greonberg, Guillaume Lettre, John R. Thompson, Inês Barroso, John R. B. Perry, Andreas Ziegler, James F. Wilson, Christopher J. O'Donnell, Maurizio F. Facheris, Robert Lawrence, Jan Smit, Lyle J. Palmer, Ulf Gyllensten, Richard B. Hayes, Shengxu Li, Barbara Ludwig, Larry D. Atwood, Valgerdur Steinthorsdottir, Sabine Schipf, Jouko Saramies, Tanja Boes, Martin Ridderstråle, Jennie Hui, Lina Zgaga, Susann Scherag, Alexandra I. F. Blakemore, Marjolein Peters, Timo T. Valle, Nelson B. Freimer, Kay-Tee Khaw, Amy J. Swift, Michael Stumvoll, Miriam F. Moffatt, Cecilia M. Lindgren, Ayellet V. Segrè, Neil Robertson, Richard N. Bergman, Francis S. Collins, Ryan P. Welch, Mari-Liis Tammesoo, Devin Absher, Tamara B. Harris, Kari E. North, Manuela Uda, Karen L. Mohlke, Inga Prokopenko, Per Hall, Gudmar Thorleifsson, Marjo-Riitta Järvelin, Guillaume Paré, Stefan Gaget, G. Bragi Walters, Michael N. Weedon, Jean-Claude Tardif, Mary F. Feitosa, Anke Toenjes, Ken K. Ong, Cécile Lecoeur, Paavo Zitting, David S. Siscovick, Chih-Mei Chen, Peter Almgren, Anneli Pouta, Philippe Froguel, Pekka Jousilahti, Jaakko Kaprio, Maria Teresa Sciarrone Alibrandi, Sophie van Wingerden, Steven A. McCarroll, Oluf Pedersen, Shaun Purcell, Veronique Vitart, Leena Kinnunen, Markus Perola, Jacques S. Beckmann, Vincent Vatin, Christopher J. Groves, Zoltán Kutalik, Lu Qi, Volker Hoesel, Seppo Koskinen, Suzanne Rafelt, Anke Hinney, Annette Peters, David Schlessinger, Eero Kajantie, Jian Yang, Nicholas G. Martin, Joshua W. Knowles, Kristian Midthjell, Olivier Lantieri, Dorret I. Boomsma, Harry Campbell, Ulrich John, Kirsi H. Pietilaeinen, George Davey Smith, Carl G. P. Platou, Sarah H. Wild, Patricia B. Munroe, Iris M. Heid, Diana Marek, Michael Boehnke, Andres Metspalu, Hana Lango Allen, Peter Rzehak, Christine Cavalcanti-Proença, M. Carola Zillikens, Åsa Johansson, Anuj Goel, Andrew T. Hattersley, Massimo Mangino, Michael E. Goddard, Tim D. Spector, Winfried Rief, Jonathan Tyrer, Lachlan J. M. Coin, Peter P. Pramstaller, Narisu Narisu, John Beilby, Jonathan Stephens, Christina Barlassina, Pamela Fischer-Posovszky, Brenda W.J.H. Penninx, Kaisa Silander, Richard H. Myers, Jouke-Jan Hottenga, Eric E. Schadt, Francesco P. Cappuccio, Martin den Heijer, Fernando Rivadeneira, Lindsay L. Waite, Wilmar Igl, Igor Rudan, Manjinder S. Sandhu, Debbie A Lawlor, Kristian Hveem, Susanna Wiegand, Mari Nelis, Thomas Reinehr, Elisabeth Thiering, Inke R. Koenig, Stephan B. Felix, Fredrik Wiklund, Ian N. M. Day, Willem H. Ouwehand, Peter Schwarz, Richard M. Watanabe, Keri L. Monda, Kari Stefansson, Gudny Eiriksdottir, H-Erich Wichmann, Jianxin Shi, Najaf Amin, Carlos Iribarren, Heiko Krude, Dale R. Nyholt, Lenore J. Launer, Stephen J. Chanock, Harald Grallert, Hugh Watkins, Juergen Graessler, Tsegaselassie Workalemahu, Jeanette Erdmann, Mattias Lorentzon, Leif Groop, Teresa Ferreira, Chiara Lanzani, Johanna Kuusisto, Johan G. Eriksson, Tõnu Esko, Torben Jørgensen, Robert J. Weyant, Michael Preuss, Lambertus A. Kiemeney, Daniel I. Chasman, Daniel R. Witte, Kevin B. Jacobs, Nicole Soranzo, John M. C. Connell, Soumya Raychaudhuri, Jian'an Luan, Joshua C. Randall, Joachim Heinrich, Anthony J. Balmforth, Eva Fisher, Elizabeth S. Jewell, Alice M. Arnold, Nele Friedrich, Olli T. Raitakari, Henri Wallaschofski, Jeffrey R. O'Connell, Terho Lehtimaeki, Marika Kaakinen, Heather M. Stringham, Bo Isomaa, I. Sadaf Farooqi, Anna L. Dixon, Anne U. Jackson, Mark I. McCarthy, Lori L. Bonnycastle, Aila Rissanen, Joel N. Hirschhorn, Nilesh J. Samani, Aimo Ruokonen, Frank B. Hu, L. Adrienne Cupples, Amanda J. Bennett, Shamika Ketkar, Ruth J. F. Loos, Nicholas J. Wareham, Tiinamaija Tuomi, Timothy M. Frayling, Ulla Sovio, Georg Homuth, Liming Liang, Heiner Boeing, Unnur Thorsteinsdottir, Ingrid B. Borecki, Danielle M. Greenawalt, Rosanda Mulić, Ivana Kolcic, Talin Haritunians, Mark J. Caulfield, Marja-Liisa Lokki, Tanya M. Teslovich, Paul Elliott, Matt Neville, Nilanjan Chatterjee, Albert V. Smith, Andrew P. Morris, Fabio Busonero, Gonçalo R. Abecasis, Jaana Laitinen, Michael R. Erdos, Candace Guiducci, Lee M. Kaplan, Aki S. Havulinna, Pablo V. Gejman, Alan R. Shuldiner, Serena Sanna, David J. Hunter, Sonja I. Berndt, Carla I. G. Vogel, Alistair S. Hall, Karol Estrada, Sven Bergmann, Thomas Meitinger, Gonneke Willemsen, Andrew C. Heath, Katja K.H. Aben, Markku Laakso, Juha Sinisalo, Tuomas O. Kilpelaenen, Mark E. Cooper, Heike Biebermann, Eco J. C. de Geus, Grant W. Montgomery, Sophie Visvikis-Siest, Thomas W. Winkler, Ju-Hyun Park, Alex N. Parker, Peter S. Chines, James Nemesh, Nabila Bouatia-Naji, Wendy L. McArdle, Roberto Elosua, Markku S. Nieminen, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Epidemiology, Internal Medicine, Clinical Genetics, Radiology & Nuclear Medicine, Erasmus MC other, Public Health, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, MAGIC, Procardis Consortium, Medical Research Council (MRC), Speliotes, Ek, Willer, Cj, Berndt, Si, Monda, Kl, Thorleifsson, G, Jackson, Au, Allen, Hl, Lindgren, Cm, Luan, J, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Qi, L, Workalemahu, T, Heid, Im, Steinthorsdottir, V, Stringham, Hm, Weedon, Mn, Wheeler, E, Wood, Ar, Ferreira, T, Weyant, Rj, Segrè, Av, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Gustafsson, S, Kilpeläinen, To, Yang, J, BOUATIA NAJI, N, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Raychaudhuri, S, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Amin, N, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, HEARD COSTA, Nl, Hoesel, V, Hottenga, Jj, Johansson, A, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Narisu, N, Perry, Jr, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Scott, Lj, Timpson, Nj, Tyrer, Jp, VAN WINGERDEN, S, Watanabe, Rm, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Prokopenko, I, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Almgren, P, Arnold, Am, Aspelund, T, Atwood, Ld, Balkau, B, Balmforth, Aj, Bennett, Aj, BEN SHLOMO, Y, Bergman, Rn, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bonnycastle, Ll, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Campbell, H, Cappuccio, Fp, CAVALCANTI PROENÇA, C, Chen, Yd, Chen, Cm, Chines, P, Clarke, R, Coin, L, Connell, J, Day, In, DEN HEIJER, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Erdos, Mr, Eriksson, Jg, Facheris, Mf, Felix, Sb, FISCHER POSOVSZKY, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gieger, C, Gjesing, Ap, Goel, A, Goyette, P, Grallert, H, Grässler, J, Greenawalt, Dm, Groves, Cj, Gudnason, V, Guiducci, C, Hartikainen, Al, Hassanali, N, Hall, A, Havulinna, A, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Hofman, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Isomaa, B, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kajantie, E, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kuusisto, J, Kraft, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Lehtimäki, T, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, Paolo, Marek, D, Marre, M, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Meitinger, T, Melander, O, Meyre, D, Midthjell, K, Montgomery, Gw, Morken, Ma, Morris, Ap, Mulic, R, Ngwa, J, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Robertson, Nr, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, M, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, D, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Swift, Aj, Tammesoo, Ml, Tardif, Jc, TEDER LAVING, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, Tuomi, T, VAN MEURS, Jb, VAN OMMEN, Gj, Vatin, V, Viikari, J, VISVIKIS SIEST, S, Vitart, V, Vogel, Ci, Voight, Bf, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, I, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, M, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, J, Boeing, H, Boerwinkle, E, Boomsma, Di, Caulfield, Mj, Chanock, Sj, Collins, F, Cupples, La, Smith, Gd, Erdmann, J, Froguel, P, Grönberg, H, Gyllensten, U, Hall, P, Hansen, T, Harris, Tb, Hattersley, At, Hayes, Rb, Heinrich, J, Hu, Fb, Hveem, K, Illig, T, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Laakso, M, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Pedersen, O, Penninx, Bw, Peters, A, Pramstaller, Pp, Quertermous, T, Reinehr, T, Rissanen, A, Rudan, I, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Tuomilehto, J, Uda, M, Uitterlinden, A, Valle, Tt, Wabitsch, M, Waeber, G, Wareham, Nj, Watkins, H, Procardis, Consortium, Wilson, Jf, Wright, Af, Zillikens, Mc, Chatterjee, N, Mccarroll, Sa, Purcell, S, Schadt, Ee, Visscher, Pm, Assimes, Tl, Borecki, Ib, Deloukas, P, Fox, C, Groop, Lc, Haritunians, T, Hunter, Dj, Kaplan, Rc, Mohlke, Kl, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, VAN DUIJN, Cm, Wichmann, He, Frayling, Tm, Thorsteinsdottir, U, Abecasis, Gr, Barroso, I, Boehnke, M, Stefansson, K, North, Ke, Mccarthy, Mi, Hirschhorn, Jn, Ingelsson, E, and Loos, Rj
Subjects: Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], FTO gene, Body Mass Index, 0302 clinical medicine, SH2B1, GASTRIC-INHIBITORY POLYPEPTIDE, ADULT OBESITY, Glucose homeostasis, Body Size, GENETICS & HEREDITY, 2. Zero hunger, Genetics, Genetics & Heredity, RISK, 0303 health sciences, Neuronal growth regulator 1, Genetics of obesity, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Body Height/genetics, Body Size/genetics, Body Weight/genetics, European Continental Ancestry Group/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Humans, Obesity/genetics, Polymorphism, Single Nucleotide, FAT MASS, Body Height/*genetics *Body Mass Index Body Size/genetics Body Weight/*genetics *Chromosome Mapping European Continental Ancestry Group/genetics Genetic Predisposition to Disease/genetics Genome-Wide Association Study Humans Obesity/genetics Polymorphism, Single Nucleotide, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, MELANOCORTIN-4 RECEPTOR GENE, Life Sciences & Biomedicine, European Continental Ancestry Group, EARLY-ONSET, 030209 endocrinology & metabolism, Locus (genetics), Biology, Article, White People, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, body mass index, genome-wide association, meta-analysis, Genetic Predisposition to Disease, Obesity, GENOME-WIDE ASSOCIATION, FTO GENE, 030304 developmental biology, Science & Technology, genome-wide association gastric-inhibitory polypeptide melanocortin-4 receptor gene glucose-homeostasis common variants adult obesity early-onset fat mass risk metaanalysis, Body Weight, 06 Biological Sciences, MAGIC, Body Height, GLUCOSE-HOMEOSTASIS, Procardis Consortium, Body mass index, Developmental Biology
Abstract: Obesity is globaLy prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined aSociations betwEn body maS index and ĝ̂1/42.8 miLion SNPs in up to 123,865 individuals with targeted foLow up of 42 SNPs in up to 125,931 aDitional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci aSociated with body maS index (P < 5-10-8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly aSociated loci may provide new insights into human body weight regulation. © 2010 Nature America, Inc. All rights reserved.
Published: 2010

46. Running against the clock: a qualitative study of internal medicine residents’ work experience

Author: Céline Bourquin, Matteo Monti, Michael Saraga, Friedrich Stiefel, Vanessa Kraege, David Gachoud, Julien Castioni, Pedro-Manuel Marques-Vidal, François Bastardot, Marie Méan, Olivier Lamy, Peter Vollenweider, Gérard Waeber, and Antoine Garnier
Subjects: Medicine
Abstract: AIM OF THE STUDY: While hospitals are adopting strategies designed to increase the overall efficiency of the healthcare system, physicians are facing expanding requirements. Such changes in work environment add new psychosocial and physical stressors. Building on a previous quantitative time-motion study, we conducted a qualitative study to better understand the work experience of internal medicine residents. METHODS: The study used a qualitative description approach, and was based on focus group discussions with residents. Data were analysed using reflexive thematic analysis. The study was conducted among all residents of the Internal Medicine division of a tertiary university hospital in Switzerland. RESULTS: Time emerged as the major determinant of residents’ daily experience, which residents want to waste on no account. Shifts are perceived as a constraining succession of distinct periods, with little room for adjustments. Moreover, residents feel held back and distracted in their progression toward the end of the shift. Under time pressure, some essential professional activities, such as caring for patients and families, dealing with medical complications and talking with consultants, may be experienced as unexpected undesirable bumps on the road. Residents describe “running through” a structured day, scattered with obstacles, and resorting to “tricks of the trade” in an attempt to influence the course of the shift. CONCLUSIONS: Time constraints are not new to medicine. However, our findings outline how time has become a constant preoccupation for internal medicine residents, permeating their daily work experience. This changing relationship with time carries the risk of undermining the foundations of clinical medicine and challenges the ability of hospitals to preserve the “sense of the profession”.
Published: 2022
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47. Effect of acute iron infusion on insulin secretion: A randomized, double-blind, placebo-controlled trial

Author: Evrim Jaccard, Kévin Seyssel, Alexandre Gouveia, Catherine Vergely, Laila Baratali, Cédric Gubelmann, Marc Froissart, Bernard Favrat, Pedro Marques-Vidal, Luc Tappy, and Gérard Waeber
Subjects: Type 2 diabetes, Insulin secretion, Insulin sensitivity, Iron deficiency, Iron sufficiency, Inflammation, Medicine (General), R5-920
Abstract: Summary: Background: Chronic exposure to high iron levels increases diabetes risk partly by inducing oxidative stress, but the consequences of acute iron administration on beta cells are unknown. We tested whether the acute administration of iron for the correction of iron deficiency influenced insulin secretion and the production of reactive oxygen species. Methods: Single-center, double-blinded, randomized controlled trial conducted between June 2017 and March 2020. 32 women aged 18 to 47 years, displaying symptomatic iron deficiency without anaemia, were recruited from a community setting and randomly allocated (1:1) to a single infusion of 1000 mg intravenous ferric carboxymaltose (iron) or saline (placebo). The primary outcome was the between group mean difference from baseline to day 28 in first and second phase insulin secretion, assessed by a two-step hyperglycaemic clamp. All analyses were performed by intention to treat. This trial was registered in ClinicalTrials.gov NCT03191201. Findings: Iron infusion did not affect first and second phase insulin release. For first phase, the between group mean difference from baseline to day 28 was 0 μU × 10 min/mL [95% CI, -22 to 22, P = 0.99]. For second phase, it was -5 μUx10min/mL [95% CI, -161 to 151; P = 0.95] at the first plateau of the clamp and -249 μUx10min/mL [95% CI, -635 to 137; P = 0.20] at the second plateau. Iron infusion increased serum ascorbyl/ascorbate ratio, a marker of plasma oxidative stress, at day 14, with restoration of normal ratio at day 28 relative to placebo. Finally, high-sensitive C-reactive protein levels remained similar among groups. Interpretation: In iron deficient women without anaemia, intravenous administration of 1000 mg of iron in a single sitting did not impair glucose-induced insulin secretion despite a transient increase in the levels of circulating reactive oxygen species. Funding: The Swiss National Science Foundation, University of Lausanne and Leenaards, Raymond-Berger and Placide Nicod Foundations.
Published: 2022
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48. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Author: François Pattou, Thomas Sparsø, Eleftheria Zeggini, Michael N. Weedon, J. Graessler, Mandy van Hoek, Suzette J. Bielinski, Amy J. Swift, David S. Siscovick, Michael R. Erdos, Kenneth Rice, Nabila Bouatia-Naji, Benjamin F. Voight, Wolfgang Rathmann, Jarred B. McAteer, Caroline S. Fox, Kari Stefansson, Vincent Mooser, Philippe Froguel, Gordon H. Williams, Mike Sampson, Annelli Sandbæk, Jeffrey R. O'Connell, Stefan R. Bornstein, Robert Sladek, Andrew D. Morris, Torben Jørgensen, Suzannah Bumpstead, Ruth E. Pakyz, James B. Meigs, Denis Rybin, Peter Vollenweider, Valle Tt, Andrew T. Hattersley, Amélie Bonnefond, Knut Krohn, Kijoung Song, Erik Ingelsson, Mario A. Morken, Laura J. Scott, Richard M. Watanabe, Eric J.G. Sijbrands, David Altshuler, Harald Grallert, Vladimir Mayor, Yii-Der Ida Chen, Heather M. Stringham, Bruce M. Psaty, Andrew B. Singleton, Nicole L. Glazer, Peter Schwarz, Jaakko Tuomilehto, Mathieu Firmann, Yvonne Böttcher, Knut Borch-Johnsen, Josée Dupuis, Unnur Thorsteinsdottir, Thomas A. Buchanan, Avan Aihie Sayer, Inga Prokopenko, Thomas Illig, Inês Barroso, Aroon D. Hingorani, Daniel S. Pearson, Luigi Ferrucci, Anna Köttgen, H.-Erich Wichmann, Peter Shrader, Yurii S. Aulchenko, Lu Qi, Olivier Le Bacquer, Eric J. Brunner, Meena Kumari, Karen L. Mohlke, Valgerdur Steinthorsdottir, Laura Pascoe, Lori L. Bonnycastle, Francis S. Collins, Jérôme Delplanque, Guillaume Charpentier, Michael Stumvoll, Mark O. Goodarzi, Felicity Payne, Ruth J. F. Loos, Richard N. Bergman, Gudmar Thorleifsson, Beverley Balkau, Jing Hua Zhao, Timothy M. Frayling, Josephine M. Egan, Kristin Ardlie, Stephen J. Sharp, Jalal Taneera, Mark Walker, W. H. Linda Kao, Nicholas L. Smith, Niels Grarup, Nita G. Forouhi, Oluf Pedersen, Cécile Lecoeur, Andrew Walley, Ann-Christine Syvänen, Eric Boerwinkle, Toby Johnson, Camilla H. Andreasen, Jian Anluan, Dawn M. Waterworth, Toshiko Tanaka, Braxton D. Mitchell, Alisa K. Manning, James S. Pankow, Valeriya Lyssenko, Mika Kivimäki, David Couper, Alex S. F. Doney, Nicholas J. Wareham, Tiinamaija Tuomi, Johanna Kuusisto, Torben Hansen, Christine Cavalcanti-Proença, Richa Saxena, Markku Laakso, James F. Wilson, Bo Isomaa, Marilyn C. Cornelis, David Meyre, Anne U. Jackson, Holly E. Syddall, Alan R. Shuldiner, Michael Boehnke, Peter M. Nilsson, Gabriel Crawford, Claudia Langenberg, Jerome I. Rotter, Peter S. Chines, Cyrus Cooper, Peter Kovacs, Torsten Lauritzen, Christian Dina, Gerard Waeber, Man Li, Anke Tönjes, Narisu Narisu, Jose C. Florez, David M. Nathan, Leif Groop, Claire Levy-Marchal, Cornelia M. van Duijn, Mark I. McCarthy, Frank B. Hu, Trine Welløv Boesgaard, Colin N. Apalmer, Michael Marmot, GIANT consortium, MAGIC investigators, Ophthalmology, Internal Medicine, and Epidemiology
Subjects: Adenylate Cyclase, Male, medicine.medical_specialty, medicine.medical_treatment, Denmark, Incretin, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Carbohydrate metabolism, Incretins, Polymorphism, Single Nucleotide, Article, Body Mass Index, Receptors, Gastrointestinal Hormone, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Internal medicine, Diabetes mellitus, medicine, Genetics, Humans, Insulin, RNA, Messenger, 030304 developmental biology, 0303 health sciences, Glucose tolerance test, medicine.diagnostic_test, Gene Expression Profiling, Genetic Variation, Proteins, Glucose Tolerance Test, medicine.disease, Adenylate Cyclase/genetics, Denmark%22">Type="Geographic">Denmark, Diabetes Mellitus, Type 2/genetics, Female, Gene Expression Regulation, Genetic Loci/genetics, Genome-Wide Association Study, Glucose/metabolism, Incretins/genetics, Insulin/metabolism, Polymorphism, Single Nucleotide/genetics, Proteins/genetics, RNA, Messenger/genetics, RNA, Messenger/metabolism, Receptors, Gastrointestinal Hormone/genetics, Receptors, Gastrointestinal Hormone/metabolism, Colaus Study, Glucagon-like peptide-1, Endocrinology, Glucose, Diabetes Mellitus, Type 2, Genetic Loci, TCF7L2, Adenylyl Cyclases
Abstract: Udgivelsesdato: 2010-Feb Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
Published: 2010

49. Novel testis germ cell-specific transcript of the CREB gene contains an alternatively spliced exon with multiple in-frame stop codons

Author: Gerard Waeber and Joel F. Habener
Subjects: Male, Reading Frames, Transcription, Genetic, RNA Splicing, Molecular Sequence Data, CREB, Exon, Endocrinology, Testis, medicine, Animals, Codon, Cyclic AMP Response Element-Binding Protein, Gene, Messenger RNA, biology, Alternative splicing, RNA, Exons, Molecular biology, Stop codon, Rats, Germ Cells, medicine.anatomical_structure, biology.protein, Oligonucleotide Probes, Germ cell
Abstract: The gene encoding the cAMP-responsive transcription factor CREB consists of multiple small exons some of which undergo alternative RNA splicing. We describe the finding of a novel transcript of the CREB gene expressed at high levels in the germ cells of the rat testis. The transcript contains an alternatively spliced exon inserted within the sequence encoding the transcriptional transactivation domain of CREB and this exon contains multiple in-frame stop codons. Furthermore, the exon is conserved in both rat and human genes (75% nucleotide identity). Although the function(s) of this RNA or the truncated CREB protein predicted to result from the translation of this unusual transcript is unknown, the high level of expression in the testicular germ cells and remarkable conservation of sequences in rat and human suggests that it may have a unique biological function in these cells.
Published: 1992

50. Genetic Loci Influencing C-reactive Protein Levels and Risk of Coronary Heart Disease

Author: James Scott, Leena Peltonen, Martin Farrall, Weihua Zhang, Derrick A Bennett, Peter Vollenweider, Lachlan J. M. Coin, Jeanette Erdmann, Deborah Ashby, James C. Engert, Peter S. Braund, Gerard Waeber, Shahrul Mt-Isa, Sonia S. Anand, John C. Chambers, Noha Lim, Ian J. Brown, Aimo Ruokonen, Dawn Waterworth, Paul Elliott, Rory Collins, Vincent Mooser, Nelson B. Freimer, Robert Clarke, Marjo-Riitta Järvelin, Anders Hamsten, Mark I. McCarthy, Nilesh J. Samani, Heribert Schunkert, Philippe Froguel, J C Hopewell, Jaspal S. Kooner, Alistair S. Hall, John F. Peden, Ioanna Tzoulaki, and Hugh Watkins
Subjects: Adult, Male, C-Reactive Protein/*genetics/metabolism, Coronary Disease/blood/epidemiology/*genetics, medicine.medical_specialty, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Coronary Disease, 030204 cardiovascular system & hematology, Gastroenterology, Polymorphism, Single Nucleotide, Aged, C-Reactive Protein/genetics, C-Reactive Protein/metabolism, Coronary Disease/blood, Coronary Disease/epidemiology, Coronary Disease/genetics, Female, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Middle Aged, Molecular Epidemiology, Risk Factors, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Mendelian randomization, Medicine, SNP, 030304 developmental biology, 0303 health sciences, biology, business.industry, C-reactive protein, General Medicine, Odds ratio, 3. Good health, Surgery, Minor allele frequency, C-Reactive Protein, Nested case-control study, biology.protein, business
Abstract: CONTEXT: Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. OBJECTIVE: To investigate association of genetic loci with CRP levels and risk of coronary heart disease. DESIGN, SETTING, AND PARTICIPANTS: We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. MAIN OUTCOME MEASURE: Risk of coronary heart disease. RESULTS: Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. CONCLUSION: The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease. JAMA
Published: 2009

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