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Find video protocols related to scientific articles indexed in Pubmed.
Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension.
Ann Hepatol
PUBLISHED: 10-22-2014
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Background. Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. Material and methods. PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. Results. Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). Conclusion. Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.
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Epileptic Seizure Classification of EEG time-series using Rational Discrete Short Time Fourier Transform.
IEEE Trans Biomed Eng
PUBLISHED: 09-30-2014
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A system for epileptic seizure detection in Electroencephalography (EEG) is described in the paper. One of the challenges is to distinguish rhythmic discharges from nonstationary patterns occurring during seizures. The proposed approach is based on an adaptive and localized time-frequency representation of EEG signals by means of rational functions. The corresponding rational Discrete Short Time Fourier Transform (DSTFT) is a novel feature extraction technique for epileptic EEG data. A Multilayer Perceptron (MLP) classifier is fed by the coefficients of the rational DSTFT in order to separate seizure epochs from seizure-free epochs. The effectiveness of the proposed method is compared with several state-of-art feature extraction algorithms used in off-line epileptic seizure detection. The results of the comparative evaluations show that the proposed method outperforms competing techniques in terms of classification accuracy. In addition, it provides a compact representation of EEG time-series.
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Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.
Gut
PUBLISHED: 09-24-2014
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Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort.
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Defining the role of common variation in the genomic and biological architecture of adult human height.
Andrew R Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H Pers, Stefan Gustafsson, Audrey Y Chu, Karol Estrada, Jian'an Luan, Zoltan Kutalik, Najaf Amin, Martin L Buchkovich, Damien C Croteau-Chonka, Felix R Day, Yanan Duan, Tove Fall, Rudolf Fehrmann, Teresa Ferreira, Anne U Jackson, Juha Karjalainen, Ken Sin Lo, Adam E Locke, Reedik Mägi, Evelin Mihailov, Eleonora Porcu, Joshua C Randall, André Scherag, Anna A E Vinkhuyzen, Harm-Jan Westra, Thomas W Winkler, Tsegaselassie Workalemahu, Jing Hua Zhao, Devin Absher, Eva Albrecht, Denise Anderson, Jeffrey Baron, Marian Beekman, Ayse Demirkan, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Ross M Fraser, Anuj Goel, Jian Gong, Anne E Justice, Stavroula Kanoni, Marcus E Kleber, Kati Kristiansson, Unhee Lim, Vaneet Lotay, Julian C Lui, Massimo Mangino, Irene Mateo Leach, Carolina Medina-Gomez, Michael A Nalls, Dale R Nyholt, Cameron D Palmer, Dorota Pasko, Sonali Pechlivanis, Inga Prokopenko, Janina S Ried, Stephan Ripke, Dmitry Shungin, Alena Stančáková, Rona J Strawbridge, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W van der Laan, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Zhaoming Wang, Loïc Yengo, Weihua Zhang, Uzma Afzal, Johan Arnlöv, Gillian M Arscott, Stefania Bandinelli, Amy Barrett, Claire Bellis, Amanda J Bennett, Christian Berne, Matthias Blüher, Jennifer L Bolton, Yvonne Böttcher, Heather A Boyd, Marcel Bruinenberg, Brendan M Buckley, Steven Buyske, Ida H Caspersen, Peter S Chines, Robert Clarke, Simone Claudi-Boehm, Matthew Cooper, E Warwick Daw, Pim A de Jong, Joris Deelen, Graciela Delgado, Josh C Denny, Rosalie Dhonukshe-Rutten, Maria Dimitriou, Alex S F Doney, Marcus Dörr, Niina Eklund, Elodie Eury, Lasse Folkersen, Melissa E Garcia, Frank Geller, Vilmantas Giedraitis, Alan S Go, Harald Grallert, Tanja B Grammer, Jürgen Gräßler, Henrik Grönberg, Lisette C P G M de Groot, Christopher J Groves, Jeffrey Haessler, Per Hall, Toomas Haller, Göran Hallmans, Anke Hannemann, Catharina A Hartman, Maija Hassinen, Caroline Hayward, Nancy L Heard-Costa, Quinta Helmer, Gibran Hemani, Anjali K Henders, Hans L Hillege, Mark A Hlatky, Wolfgang Hoffmann, Per Hoffmann, Oddgeir Holmen, Jeanine J Houwing-Duistermaat, Thomas Illig, Aaron Isaacs, Alan L James, Janina Jeff, Berit Johansen, Asa Johansson, Jennifer Jolley, Thorhildur Juliusdottir, Juhani Junttila, Abel N Kho, Leena Kinnunen, Norman Klopp, Thomas Kocher, Wolfgang Kratzer, Peter Lichtner, Lars Lind, Jaana Lindström, Stéphane Lobbens, Mattias Lorentzon, Yingchang Lu, Valeriya Lyssenko, Patrik K E Magnusson, Anubha Mahajan, Marc Maillard, Wendy L McArdle, Colin A McKenzie, Stela McLachlan, Paul J McLaren, Cristina Menni, Sigrun Merger, Lili Milani, Alireza Moayyeri, Keri L Monda, Mario A Morken, Gabriele Müller, Martina Müller-Nurasyid, Arthur W Musk, Narisu Narisu, Matthias Nauck, Ilja M Nolte, Markus M Nöthen, Laticia Oozageer, Stefan Pilz, Nigel W Rayner, Frida Renstrom, Neil R Robertson, Lynda M Rose, Ronan Roussel, Serena Sanna, Hubert Scharnagl, Salome Scholtens, Fredrick R Schumacher, Heribert Schunkert, Robert A Scott, Joban Sehmi, Thomas Seufferlein, Jianxin Shi, Karri Silventoinen, Johannes H Smit, Albert Vernon Smith, Joanna Smolonska, Alice V Stanton, Kathleen Stirrups, David J Stott, Heather M Stringham, Johan Sundström, Morris A Swertz, Ann-Christine Syvänen, Bamidele O Tayo, Gudmar Thorleifsson, Jonathan P Tyrer, Suzanne van Dijk, Natasja M van Schoor, Nathalie van der Velde, Diana van Heemst, Floor V A van Oort, Sita H Vermeulen, Niek Verweij, Judith M Vonk, Lindsay L Waite, Melanie Waldenberger, Roman Wennauer, Lynne R Wilkens, Christina Willenborg, Tom Wilsgaard, Mary K Wojczynski, Andrew Wong, Alan F Wright, Qunyuan Zhang, Dominique Arveiler, Stephan J L Bakker, John Beilby, Richard N Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Dorret I Boomsma, Stefan R Bornstein, Pascal Bovet, Paolo Brambilla, Morris J Brown, Harry Campbell, Mark J Caulfield, Aravinda Chakravarti, Rory Collins, Francis S Collins, Dana C Crawford, L Adrienne Cupples, John Danesh, Ulf de Faire, Hester M den Ruijter, Raimund Erbel, Jeanette Erdmann, Johan G Eriksson, Martin Farrall, Ele Ferrannini, Jean Ferrières, Ian Ford, Nita G Forouhi, Terrence Forrester, Ron T Gansevoort, Pablo V Gejman, Christian Gieger, Alain Golay, Omri Gottesman, Vilmundur Gudnason, Ulf Gyllensten, David W Haas, Alistair S Hall, Tamara B Harris, Andrew T Hattersley, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Lucia A Hindorff, Aroon D Hingorani, Albert Hofman, G Kees Hovingh, Steve E Humphries, Steven C Hunt, Elina Hyppönen, Kevin B Jacobs, Marjo-Riitta Järvelin, Pekka Jousilahti, Antti M Jula, Jaakko Kaprio, John J P Kastelein, Manfred Kayser, Frank Kee, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Jaspal S Kooner, Charles Kooperberg, Seppo Koskinen, Peter Kovacs, Aldi T Kraja, Meena Kumari, Johanna Kuusisto, Timo A Lakka, Claudia Langenberg, Loic Le Marchand, Terho Lehtimäki, Sara Lupoli, Pamela A F Madden, Satu Mannisto, Paolo Manunta, André Marette, Tara C Matise, Barbara McKnight, Thomas Meitinger, Frans L Moll, Grant W Montgomery, Andrew D Morris, Andrew P Morris, Jeffrey C Murray, Mari Nelis, Claes Ohlsson, Albertine J Oldehinkel, Ken K Ong, Willem H Ouwehand, Gerard Pasterkamp, Annette Peters, Peter P Pramstaller, Jackie F Price, Lu Qi, Olli T Raitakari, Tuomo Rankinen, D C Rao, Treva K Rice, Marylyn Ritchie, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Jouko Saramies, Mark A Sarzynski, Peter E H Schwarz, Sylvain Sebert, Peter Sever, Alan R Shuldiner, Juha Sinisalo, Valgerdur Steinthorsdottir, Ronald P Stolk, Jean-Claude Tardif, Anke Tönjes, Angelo Tremblay, Elena Tremoli, Jarmo Virtamo, Marie-Claude Vohl, , Philippe Amouyel, Folkert W Asselbergs, Themistocles L Assimes, Murielle Bochud, Bernhard O Boehm, Eric Boerwinkle, Erwin P Bottinger, Claude Bouchard, Stéphane Cauchi, John C Chambers, Stephen J Chanock, Richard S Cooper, Paul I W de Bakker, George Dedoussis, Luigi Ferrucci, Paul W Franks, Philippe Froguel, Leif C Groop, Christopher A Haiman, Anders Hamsten, M Geoffrey Hayes, Jennie Hui, David J Hunter, Kristian Hveem, J Wouter Jukema, Robert C Kaplan, Mika Kivimäki, Diana Kuh, Markku Laakso, Yongmei Liu, Nicholas G Martin, Winfried März, Mads Melbye, Susanne Moebus, Patricia B Munroe, Inger Njølstad, Ben A Oostra, Colin N A Palmer, Nancy L Pedersen, Markus Perola, Louis Pérusse, Ulrike Peters, Joseph E Powell, Chris Power, Thomas Quertermous, Rainer Rauramaa, Eva Reinmaa, Paul M Ridker, Fernando Rivadeneira, Jerome I Rotter, Timo E Saaristo, Danish Saleheen, David Schlessinger, P Eline Slagboom, Harold Snieder, Tim D Spector, Konstantin Strauch, Michael Stumvoll, Jaakko Tuomilehto, Matti Uusitupa, Pim van der Harst, Henry Völzke, Mark Walker, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Pieter Zanen, Panos Deloukas, Iris M Heid, Cecilia M Lindgren, Karen L Mohlke, Elizabeth K Speliotes, Unnur Thorsteinsdottir, Inês Barroso, Caroline S Fox, Kari E North, David P Strachan, Jacques S Beckmann, Sonja I Berndt, Michael Boehnke, Ingrid B Borecki, Mark I McCarthy, Andres Metspalu, Kari Stefansson, André G Uitterlinden, Cornelia M van Duijn, Lude Franke, Cristen J Willer, Alkes L Price, Guillaume Lettre, Ruth J F Loos, Michael N Weedon, Erik Ingelsson, Jeffrey R O'Connell, Gonçalo R Abecasis, Daniel I Chasman, Michael E Goddard, Peter M Visscher, Joel N Hirschhorn, Timothy M Frayling.
Nat. Genet.
PUBLISHED: 08-29-2014
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Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ?2,000, ?3,700 and ?9,500 SNPs explained ?21%, ?24% and ?29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/?-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
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Global DNA methylation levels in human adipose tissue are related to fat distribution and glucose homeostasis.
Diabetologia
PUBLISHED: 08-22-2014
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Epigenetic alterations may influence the metabolic pathways involved in human obesity. We hypothesised that global DNA methylation levels in adipose tissue might be associated with obesity and related phenotypes.
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Novel heterozygous IGF1R mutation in two brothers with developing impaired glucose tolerance.
J. Pediatr. Endocrinol. Metab.
PUBLISHED: 08-05-2014
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Abstract Infants born small for gestational age (SGA) are at risk to develop metabolic complications. Insulin-like growth factor 1 (IGF-1) resistance due to IGF-1 receptor (IGF1R) mutations is a rare genetic condition that causes proportionate growth retardation. The contribution of an impaired IGF1R function to the development of comorbidities such as disturbed glucose homeostasis is not well understood. Genetic analysis and detailed auxological, endocrine and psychological investigations in two male SGA siblings were performed. The two patients and their father bear a novel heterozygous mutation (p.Cys1248Tyr) in the IGF1R gene. Both brothers displayed very similar growth pattern before and during recombinant human growth hormone treatment, whereas oral glucose tolerance tests showed variable manifestations of progressive impaired glucose tolerance. The father had already developed type 2 diabetes mellitus. Growth retardation in our patients is likely caused by the IGF1R mutation that might predispose to disturbances of carbohydrate homeostasis. Therefore, a close metabolic monitoring of affected patients is indicated, particularly if growth hormone therapy is commenced.
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Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves' orbitopathy: A five-year follow-up study.
Autoimmunity
PUBLISHED: 07-21-2014
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Abstract The aim of this investigations was to study the effectiveness of anti-CD20 antibody therapy in Graves' orbitopathy (GO) resistant to glucocorticoids. Five patients were entered in the study. The protocol required no improvement of orbital status after a recent course of glucocorticoids. Activity of GO was confirmed by three independent techniques: clinical activity score (CAS), (99m)Tc-labeled diethylene triamine pentaacetic acid ((99m)Tc DTPA) single photon emission computed tomography and magnetic resonance imaging. Rituximab (RTX) was given as weekly infusions of 375?mg/m(2) body surface area for four weeks. The mean follow-up period was 67 (range 58-81) months. Improvement of GO has been observed in all patients: CAS before therapy was 6.5?±?1.7 and decreased to 3.4?±?1.6 by one month (p?
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Pseudopheochromocytoma induced by anxiolytic withdrawal.
Eur. J. Med. Res.
PUBLISHED: 06-30-2014
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Symptomatic paroxysmal hypertension without significantly elevated catecholamine concentrations and with no evidence of an underlying adrenal tumor is known as pseudopheochromocytoma.
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Liver-restricted Repin1 deficiency improves whole-body insulin sensitivity, alters lipid metabolism, and causes secondary changes in adipose tissue in mice.
Diabetes
PUBLISHED: 04-23-2014
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Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue and maps within a quantitative trait locus (QTL) for body weight and triglyceride (TG) levels in the rat. The QTL has further been supported as a susceptibility locus for dyslipidemia and related metabolic disorders in congenic and subcongenic rat strains. Here, we elucidated the role of Repin1 in lipid metabolism in vivo. We generated a liver-specific Repin1 knockout mouse (LRep1(-/-)) and systematically characterized the consequences of Repin1 deficiency in the liver on body weight, glucose and lipid metabolism, liver lipid patterns, and protein/mRNA expression. Hyperinsulinemic-euglycemic clamp studies revealed significantly improved whole-body insulin sensitivity in LRep1(-/-) mice, which may be due to significantly lower TG content in the liver. Repin1 deficiency causes significant changes in potential downstream target molecules including Cd36, Ppar?, Glut2 protein, Akt phosphorylation, and lipocalin2, Vamp4, and Snap23 mRNA expression. Mice with hepatic deletion of Repin1 display secondary changes in adipose tissue function, which may be mediated by altered hepatic expression of lipocalin2 or chemerin. Our findings indicate that Repin1 plays a role in insulin sensitivity and lipid metabolism by regulating key genes of glucose and lipid metabolism.
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Psychological changes in melanoma patients during ipilimumab treatment compared to low-dose interferon alpha therapy-a follow-up study of first experiences.
Pathol. Oncol. Res.
PUBLISHED: 04-09-2014
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Immuntherapies are frequently accompanied by psychological side effects. Our goals were to detect the changes of psychological factors (depression, anxiety) among melanoma patients during ipilimumab treatment. Ten ipilimumab treated melanoma patients (Group 1.) and 18 low-dose interferon-alpha treated patients (Group 2.) were compared. In our longitudinal study we measured depression (Zung Self-Rating Depression Scale) and anxiety (State-Trait Anxiety Inventory, STAI). Psychological status was tested four times: in every 3 week during ipilimumab treatment according to the relevant treatment protocol and at baseline, 1st, 3rd and 6th month of interferon therapy. No significant differences were detected at different timepoints in the level of depression or in the anxiety scale in Group 1. However significant increase of depression was found in Group 2 during the 6 months of the study. Increased levels of anxiety were found in the second timepoint in both treatment groups. This increase was only temporary and the level of anxiety returned to the baseline. In our sample no measurable psychological differences were detectable during the 12 weeks treatment period of ipilimumab. Ipilimumab seems to have fewer psychological side-effects compared to other immune therapies.
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Adipose tissue depot specific promoter methylation of TMEM18.
J. Mol. Med.
PUBLISHED: 04-04-2014
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Epigenetic processes such as dynamic promoter methylation may play a role in obesity, fat distribution and its accompanied metabolic alterations. TMEM18 is a candidate gene for body mass index (BMI) comprising the second largest effect size among all loci identified so far via GWAS. We hypothesized that differential TMEM18 gene expression in visceral (VAT) and subcutaneous adipose tissue (SAT) may be a consequence of depot specific differential methylation at the TMEM18 promoter region. Differential methylation levels may confer fat depot specific correlations with measures of obesity and fat distribution. Here, we measured TMEM18 mRNA expression in VAT and SAT from 500 subjects. A total of 146 Caucasian individuals were investigated for differential methylation levels in VAT vs. SAT at three CpG sites. Subsequently, we tested for potential correlation of methylation levels with anthropometric and metabolic parameters. (1) In 500 individuals, we observed significantly decreased mRNA expression in SAT (paired t-test, P?
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A central role for GRB10 in regulation of islet function in man.
PLoS Genet.
PUBLISHED: 04-01-2014
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Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
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Identification of genetic loci associated with different responses to high-fat diet-induced obesity in C57BL/6N and C57BL/6J substrains.
Physiol. Genomics
PUBLISHED: 04-01-2014
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We have recently demonstrated that C57BL/6NTac and C57BL/6JRj substrains are significantly different in their response to high-fat diet-induced obesity (DIO). The C57BL/6JRj substrain seems to be protected from DIO and genetic differences between C57BL/6J and C57BL/6N substrains at 11 single nucleotide polymorphism (SNP) loci have been identified. To define genetic variants as well as differences in parameters of glucose homeostasis and insulin sensitivity between C57BL/6NTac and C57BL/6JRj substrains that may explain the different response to DIO, we analyzed 208 first backcross (BC1) hybrids of C57BL/6NTac and C57BL/6JRj [(C57BL/6NTac × C57BL/6JRj)F1 × C57BL/6NTac] mice. Body weight, epigonadal and subcutaneous fat mass, circulating leptin, as well as parameters of glucose metabolism were measured after 10 wk of high-fat diet (HFD). Genetic profiling of BC1 hybrids were performed using TaqMan SNP genotyping assays. Furthermore, to assess whether SNP polymorphisms could affect mRNA level, we carried out gene expression analysis in murine liver samples. Human subcutaneous adipose tissue was used to verify murine data of SNAP29. We identified four sex-specific variants that are associated with the extent of HFD-induced weight gain and fat depot mass. BC1 hybrids carrying the combination of risk or beneficial alleles exhibit the phenotypical extremes of the parental strains. Murine and human SC expression analysis revealed Snap29 as strongest candidate. Our data indicate an important role of these loci in responsiveness to HFD-induced obesity and suggest genes of the synaptic vesicle release system such as Snap29 being involved in the regulation of high-fat DIO.
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The genetics of fat distribution.
Diabetologia
PUBLISHED: 02-18-2014
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Fat stored in visceral depots makes obese individuals more prone to complications than subcutaneous fat. There is good evidence that body fat distribution (FD) is controlled by genetic factors. WHR, a surrogate measure of FD, shows significant heritability of up to ?60%, even after adjusting for BMI. Genetic variants have been linked to various forms of altered FD such as lipodystrophies; however, the polygenic background of visceral obesity has only been sparsely investigated in the past. Recent genome-wide association studies (GWAS) for measures of FD revealed numerous loci harbouring genes potentially regulating FD. In addition, genes with fat depot-specific expression patterns (in particular subcutaneous vs visceral adipose tissue) provide plausible candidate genes involved in the regulation of FD. Many of these genes are differentially expressed in various fat compartments and correlate with obesity-related traits, thus further supporting their role as potential mediators of metabolic alterations associated with a distinct FD. Finally, developmental genes may at a very early stage determine specific FD in later life. Indeed, genes such as TBX15 not only manifest differential expression in various fat depots, but also correlate with obesity and related traits. Moreover, recent GWAS identified several polymorphisms in developmental genes (including TBX15, HOXC13, RSPO3 and CPEB4) strongly associated with FD. More accurate methods, including cardiometabolic imaging, for assessment of FD are needed to promote our understanding in this field, where the main focus is now to unravel the yet unknown biological function of these novel 'fat distribution genes'.
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Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer.
Lung Cancer
PUBLISHED: 02-14-2014
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This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC).
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
Diabetes
PUBLISHED: 12-02-2013
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Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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[Fractionated conformal stereotactic irradiation of recurrent sacral tumour. Case report and first description of the method in Hungary].
Magy Onkol
PUBLISHED: 10-11-2013
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Non-invasive procedures completing traditional surgical treatment play an increasing role in the management of central nervous system malignancies. Conformal stereotactic irradiation (radiosurgery) has become a routine method in intracranial malignancies. However, application of this modality in tumours of the spinal cord and spinal column is much more difficult to perform. It is because extracranial organs can be only inaccurately fixed, and radio-sensitivity of the spinal cord and risks of radionecrosis with ensuing paraplegia are high. A recurrent sacrum chordoma treated by means of this modality - first reported in Hungary - has been chosen for case presentation as the criteria for radiotherapy such as high dose to target volume, minimal dose to neighbouring structures highly sensitive to radiation are best met in these tumours by means of conformal stereotactic radiotherapy. On the basis of further 13 extracranial cases treated with this method one can conclude that high precision stereotactic conformal radiotherapy offers up-grade to traditional radiotherapy despite the fact that it is a time-consuming procedure. The oncological efficiency, the reduced risks of side effects and the improved quality of life due to this treatment modality compensate duly for the increased labour input.
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[Fractionated stereotactic irradiation of skull-base related tumours].
Magy Onkol
PUBLISHED: 10-11-2013
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The prognosis of the treatment of brain tumours depends on two main factors: biological nature and localisation of the neoplasm. Requirements of oncologic surgery can be met only partially if at all in neurological surgery of brain tumours. Resectability depends primarily on localisation of the neoplasms. The leading principle is preservation of fine neural structures, minimising morbidity from tissue resection with the goal of maximal tumour resection. As nervous structures and the target volume do not move in the intracranial space, large radiation doses unusual in traditional radiotherapy can be given either in one or in fractionated sessions to small targets (point-radiation) and a well-controlled radiation necrosis of the pathological tissue can be achieved. Management principles of treatment of skull-base related tumours are very similar due to high risks of functional morbidity evoked by surgical injury to the cranial nerves, brainstem structures, vessels of the Willis circle and those of the substantia perforata anterior and posterior, etc. Such tumours are neoplasms arising from the skull base, those infiltrating the cavernous sinuses, invasive pituitary tumours, those arising from the glomus jugulare, or located within the cerebello-pontine angle, etc. This manuscript intends to illustrate and prove the hypothesis by means of 4 cases that fractionated stereotactic radiotherapy (fSRT) is an important part of treatment armamentarium in the latter cases, as it is capable of exploiting both the advantages of traditional fractionated irradiation and that of the high conformality and selectivity of radiosurgery. It is capable of administering appropriate quantity of total target dose with a lower than limit dose on surrounding structures. The presentation proves that fSRT can be planned already in the phase of surgical indication as a "microsurgery-assisted radiotherapy".
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Autologous Dendritic Cell Based Adoptive Immunotherapy of Patients with Colorectal Cancer-A Phase I-II Study.
Pathol. Oncol. Res.
PUBLISHED: 10-02-2013
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Dendritic cell-based active immunotherapies of cancer patients are aimed to provoke the proliferation and differentiation of tumor-specific CD4(+) and CD8(+) T-lymphocytes towards protective effector cells. Isolation and in vitro differentiation of circulating blood monocytes has been established a reasonable platform for adoptively transferred DC-based immunotherapies. In the present study the safety and tolerability of vaccination by autologous tumor cell lysates (oncolysate)- or carcinoembriogenic antigen (CEA)-loaded DCs in patients with colorectal cancer was investigated in a phase I-II trial. The study included 12 patients with histologically confirmed colorectal cancer (Dukes B2-C stages). Six of the patients received oncolysate-pulsed, whereas the other six received recombinant CEA-loaded autologous DCs. The potential of the tumor antigen-loaded DCs to provoke the patients immune system was studied both in vivo and in vitro. The clinical outcome of the therapy evaluated after 7 years revealed that none of the six patients treated with oncolysate-loaded DCs showed relapse of colorectal cancer, whereas three out of the six patients treated with CEA-loaded DCs died because of tumor relapse. Immunization with both the oncolysate- and the CEA-loaded autologous DCs induced measurable immune responses, which could be detected in vivo by cutaneous reactions and in vitro by lymphocyte proliferation assay. Our results show that vaccination by autologous DCs loaded with autologous oncolysates containing various tumor antigens represents a well tolerated therapeutic modality in patients with colorectal cancer without any detectable adverse effects. Demonstration of the efficacy of such therapy needs further studies with increased number of patients.
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Common variants in mendelian kidney disease genes and their association with renal function.
Afshin Parsa, Christian Fuchsberger, Anna Köttgen, Conall M O'Seaghdha, Cristian Pattaro, Mariza de Andrade, Daniel I Chasman, Alexander Teumer, Karlhans Endlich, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Young J Kim, Daniel Taliun, Man Li, Mary Feitosa, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Nicole Glazer, Aaron Isaacs, Madhumathi Rao, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Asa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Couraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tonu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Edith Hofer, Frank Hu, Ayse Demirkan, Ben A Oostra, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Franco Giulianini, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Lina Zgaga, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, André G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polašek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Bénédicte Stengel, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Helen Colhoun, Alex Doney, Antonietta Robino, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Paul Mitchell, Marina Ciullo, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline Witteman, Caroline Hayward, Paul M Ridker, Murielle Bochud, Iris M Heid, David S Siscovick, Caroline S Fox, W Linda Kao, Carsten A Böger.
J. Am. Soc. Nephrol.
PUBLISHED: 09-12-2013
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Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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THOC5: a novel gene involved in HDL-cholesterol metabolism.
J. Lipid Res.
PUBLISHED: 09-10-2013
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Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ?3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identified 14 loci associated with lipid phenotypes reaching P values <10?? and confirmed significant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n(HDL) = 6041; n(LDL) = 5,995; n(TG) = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels (P = 1.78 × 10??; Z-score = -5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1, SCARB1, and ABCG8 (all P < 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels.
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Congenital pseudarthrosis of the clavicle causing thoracic outlet syndrome.
BMJ Case Rep
PUBLISHED: 08-27-2013
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A 7-year-old girl presented with an asymptomatic right supraclavicular swelling. Radiographs were interpreted as showing a non-union of her clavicle. No treatment was given at this time. However, she represented 12 years later with right upper limb pain and altered sensation. Examination revealed a positive Allens test on the right. Repeat radiographs demonstrated a pseudarthrosis of the clavicle, associated with a secondary complication of thoracic outlet syndrome with vascular and neurological complications present. Non-operative management failed to relieve her symptoms. Operative intervention successfully treated her symptoms.
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Placental gene expression patterns of endoglin (CD105) in intrauterine growth restriction.
J. Matern. Fetal. Neonatal. Med.
PUBLISHED: 08-27-2013
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Abstract Objective: In this study, we describe placental gene expression patterns of endoglin in pregnancies with intrauterine growth restriction (IUGR) compared to normal pregnancies. Methods: Placental samples were obtained from 101 pregnancies with IUGR using 140 normal pregnancy cases as control. Gene expression patterns and protein levels of the endoglin were compared between the two groups. For the gene expression analysis real-time PCR was applied, while for the estimation of placental protein level we performed Western analysis. Results: The placental endoglin gene was significantly overexpressed in the IUGR group versus the control group (Ln2(?): 1.69). The placental endoglin protein level proved to be significantly higher in case of IUGR (endoglin/?-actin ratio: 13.8?±?2.3) versus the control cases (5.3?±?1.1). The placental gene expression as well as the protein levels of endoglin showed no significant difference between female and male newborns. Concerning the placental gene expression and protein level, no significant difference was justified between the more (0-5 percentile) and less (5-10 percentile) severe cases of IUGR. Conclusion: Increased placental gene expression of endoglin may result in vascular dysfunction leading to chronic fetal hypoxia, which may induce VEGF-A to stimulate angiogenesis. This can be explained as feed back response to restore fetal placental circulation.
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Development of novel chiral capillary electrophoresis methods for the serotonin receptor (5-HT2A) antagonist MDL 100,907 (volinanserin) and for its key intermediate compound.
J Pharm Biomed Anal
PUBLISHED: 08-15-2013
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Enantioselective capillary electrophoretic methods were elaborated for the determination of the enantiomeric purity of (R)-MDL 100,907 and its preparatively resolved key intermediate compound during the synthesis route. The pKa values of the intermediate compound and the end product determined by CE were 10.5±0.1 and 9.0±0.1, respectively. The enantiopurity of the intermediate compound can be monitored in fully protonated state by applying 15mM sulfobutylether-?-cyclodextrin at pH 5 when the peak belonging to the impurity migrates before the main component. The fact that the consecutive steps of the synthesis do not affect the enantiomeric purity was verified by the other, newly developed CE method. The enantiomers of rac-MDL 100,907 were resolved by 15mM carboxymethyl-?-cyclodextrin at pH 3. The applicability (selectivity, LOD, LOQ, repeatability, precision and accuracy) of the methods was studied as well.
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Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
Joshua C Randall, Thomas W Winkler, Zoltan Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tonu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, André Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, , Amélie Bonnefond, Philippe Froguel, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Järvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimäki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, Iris M Heid.
PLoS Genet.
PUBLISHED: 06-01-2013
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Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
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SGLT2: a potential target for the pharmacogenetics of Type 2 diabetes?
Pharmacogenomics
PUBLISHED: 05-09-2013
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The kidney has attracted the attention of diabetologists as an organ involved in the regulation of glucose homeostasis not only by gluconeogenesis, but also by renal glucose excretion. Sodium-glucose cotransporters (SGLTs), particularly SGLT2, are responsible for reabsorption of up to 99% of the filtered glucose. SGLT2 is coded by the SLC5A2 gene, which maps on chromosome 16. Pharmacological reduction of tubular glucose reabsorption results in improved glycemic control in Type 2 diabetic patients. Since the SGLTs reabsorb most of the filtered glucose (90%), it is not surprising that mutations in SLC5A2 cause familial renal glucosuria. A recent study pointed out a possible role of common genetic variation in SLC5A2 in the control of glucose homeostasis. SLC5A2 polymorphisms might therefore represent potential candidates for pharmacogenomic studies targeting the impact of these variants on the efficacy of antidiabetic treatment that is based on inhibition of SGLT2 activity.
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Uridine modulates neuronal activity and inhibits spike-wave discharges of absence epileptic Long Evans and Wistar Albino Glaxo/Rijswijk rats.
Brain Res. Bull.
PUBLISHED: 04-20-2013
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Pharmacological and functional data suggest the existence of uridine (Urd) receptors in the central nervous system (CNS). In the present study, simultaneous extracellular single unit recording and microiontophoretic injection of the pyrimidine nucleoside Urd was used to provide evidence for the presence of Urd-sensitive neurons in the thalamus and the cerebral cortex of Long Evans rats. Twenty-two neurons in the thalamus (24% of recorded neurons) and 17 neurons in the cortex (55%) responded to the direct iontophoresis of Urd. The majority of Urd-sensitive neurons in the thalamus and cortex (82% and 59%, respectively) increased their firing rate in response to Urd. In contrary, adenosine (Ado) and uridine 5-triphosphate (UTP) decreased the firing rate of all responding neurons in the thalamus, and the majority of responding neurons in the cortex (83% and 87%, respectively). Functional relevance of Urd-sensitive neurons was investigated in spontaneously epileptic freely moving Long Evans and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Intraperitoneal (i.p.) injection of 500mg/kg Urd decreased epileptic activity (210-270min after injection) in both rat strains. Intraperitoneal administration of 1000mg/kg Urd decreased the number of spike-wave discharges (SWDs) between 150-270min and 90-270min in Long Evans and WAG/Rij rats, respectively. The effect of Urd was long-lasting in both rat strains as the higher dose significantly decreased the number of SWDs even 24h after Urd injection. The present results suggest that Urd-sensitive neurons in the thalamus and the cerebral cortex may play a role in the antiepileptic action of Urd possibly via modulation of thalamocortical neuronal circuits.
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Variants in CPA1 are strongly associated with early onset chronic pancreatitis.
Nat. Genet.
PUBLISHED: 04-18-2013
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Chronic pancreatitis is an inflammatory disorder of the pancreas. We analyzed CPA1, encoding carboxypeptidase A1, in subjects with nonalcoholic chronic pancreatitis (cases) and controls in a German discovery set and three replication sets. Functionally impaired variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9, P = 1.5 × 10(-16)). The association was strongest in subjects aged ? 10 years (9.7%; OR = 84.0, P = 4.1 × 10(-24)). In the replication sets, defective CPA1 variants were present in 8/600 (1.3%) cases and 9/2,432 (0.4%) controls from Europe (P = 0.01), 5/230 (2.2%) cases and 0/264 controls from India (P = 0.02) and 5/247 (2.0%) cases and 0/341 controls from Japan (P = 0.013). The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.
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Nicotinamide nucleotide transhydrogenase mRNA expression is related to human obesity.
Obesity (Silver Spring)
PUBLISHED: 04-18-2013
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A spontaneous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene eliminating exons 7-11 in C57BL/6J (B6J) mice is associated with reduced glucose-stimulated insulin secretion in vitro, impaired glucose tolerance, higher epigonadal fat mass, and altered susceptibility to diet induced obesity of male B6J mice was proposed. A potential implication for NNT in human adipose tissue distribution has not been investigated so far.
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Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency.
BMC Endocr Disord
PUBLISHED: 04-10-2013
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The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD.
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Analysis of a rare functional truncating mutation rs61757459 in vaspin (SERPINA12) on circulating vaspin levels.
J. Mol. Med.
PUBLISHED: 03-19-2013
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A recent genome-wide association study suggests that genetic variation within the vaspin gene might contribute to the variability in circulating serum visceral adipose tissue-derived serine protease inhibitor (vaspin) concentrations. Here, we analyzed the functional consequences of the rare variant rs61757459 predicting a premature stop codon and its impact on circulating serum vaspin concentrations. In order to identify genetic variation, we sequenced the vaspin gene in 48 nonrelated Caucasian subjects. Rs61757459 was subsequently genotyped in three metabolically well-characterized German cohorts (N?=?4,019). We addressed the impact of rs61757459 on the crystal structure of vaspin and investigated its effects on vaspin expression in vivo as well as in vitro using various cell lines (Escherichia coli, HEK293). Along with previously reported common genetic variants, sequencing of vaspin revealed a rare variant (rs61757459; minor allele frequency: 1 %) which predicts a premature stop codon p.R211X. Heterozygous carriers of this mutation had lower circulating vaspin levels when compared with noncarriers. In silico structure analysis of the truncated vaspin, which was estimated to be 24.5 kDa, suggested misfolding and potential instability due to the absence of core structural domains. Indeed, the truncated protein was detected after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells. We conclude that rs61757459 is a functional mutation that results in a truncated protein whose instability likely results in reduced serum vaspin levels.
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Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression.
Obesity (Silver Spring)
PUBLISHED: 03-18-2013
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Beta-site amyloid precursor protein cleaving enzyme (BACE1) is highly expressed in pancreatic ?-cells. The BACE1 gene is located in a region associated with a high diabetes risk in PIMA Indians.
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Insulin administration acutely decreases vaspin serum concentrations in humans.
Obes Facts
PUBLISHED: 03-02-2013
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It has been hypothesized that insulin might mediate meal-related diurnal variation in vaspin serum concentrations. We therefore investigated whether insulin affects serum vaspin levels in humans. Vaspin serum concentrations were determined by ELISA in 10 healthy individuals, who underwent an insulin tolerance test (ITT) for the evaluation of pituitary ACTH and growth hormone reserve. The ITTs were started 08:00 am after an overnight fast with a bolus i.v. insulin dose of 0.15 IU/kg body weight (Actrapid). Blood samples were taken at -15, 0, 15, 30, 60, 90, and 120 min after insulin administration. 15 min after insulin administration, vaspin serum concentrations decreased by 19 ± 6%, continued to decrease by 42 ± 12% at 60 min and returned to 88 ± 7% of initial values 120 min after insulin administration. Our data suggest that meal-related changes in serum vaspin concentrations might be mediated by insulin.
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Gene expression patterns of vascular endothelial growth factor (VEGF-A) in human placenta from pregnancies with intrauterine growth restriction.
J. Matern. Fetal. Neonatal. Med.
PUBLISHED: 02-13-2013
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In this study, we describe changes in gene expression pattern of vascular endothelial growth factor (VEGF)-A in human placenta obtained from pregnancies with intrauterine growth restriction using placenta from normal pregnancies as control.
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Severe hypoglycemia due to possible interaction between glibenclamide and sorafenib in a patient with hepatocellular carcinoma.
Curr Drug Saf
PUBLISHED: 01-29-2013
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There is increasing evidence that tyrosine kinase inhibitors (TKIs) have significant blood glucose lowering effects. A 70-year old Caucasian male with liver cirrhosis Child-Pugh A, advanced hepatocellular carcinoma and diabetes had a stable glycemic control being treated with glibenclamide (3.5 mg twice daily). After the first daily dose of the TKI sorafenib (800 mg) the patient experienced acute nocturnal disorientation and somnolence with a corresponding blood glucose of 37 mg/dl. After administration of glucose intravenously the neurological disturbances were completely reversible. As there was no intercurrent deterioration neither of hepatic nor of renal function, the severe hypoglycemia can likely be attributed to a drug-drug interaction of sorafenib with the sulfonylurea. The complete inhibition of the CYP2C9 and CYP3A4 mediated metabolic pathway of glibenclamide through sorafenib might have resulted in a rapid accumulation of glibenclamide. Profound blood glucose lowering effects of sorafenib might have additionally contributed to the hypoglycemic episode.
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Role of vaspin in human eating behaviour.
PLoS ONE
PUBLISHED: 01-14-2013
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The adipokine vaspin (visceral adipose tissue derived serine protease inhibitor, serpinA12) follows a meal-related diurnal variation in humans and intracerebroventricular vaspin administration leads to acutely reduced food intake in db/db mice. We therefore hypothesized that vaspin may play a role in human eating behaviour.
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An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.
PLoS ONE
PUBLISHED: 01-07-2013
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Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n?=?2021; p-additive?=?0.029) and African Americans (AAs) (n?=?177; p-additive?=?0.05), with a trend in European Americans (EAs) (n?=?512; p-additive?=?0.09), but not Germans (n?=?858; p-additive?=?0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n?=?3568; p-additive?=?0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n?=?2912) or EAs (n?=?1149); however, the T allele associated with higher BMI in the subset with BMI?30 kg/m(2) (n?=?568 EAs; p-additive?=?0.049, n?=?196 Japanese; p-additive?=?0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive?=?0.080) and 48 Hong Kong Chinese (p-additive?=?0.81) with BMI?30 kg/m(2) (n?=?1575; p-additive?=?0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive?=?0.018) and ACACB protein levels in the liver tissue (mixed model p-additive?=?0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.
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Vaspin inhibits kallikrein 7 by serpin mechanism.
Cell. Mol. Life Sci.
PUBLISHED: 01-03-2013
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The molecular target of the adipokine vaspin (visceral adipose tissue-derived serpin; serpinA12) and its mode of action are unknown. Here, we provide the vaspin crystal structure and identify human kallikrein 7 (hK7) as a first protease target of vaspin inhibited by classical serpin mechanism with high specificity in vitro. We detect vaspin-hK7 complexes in human plasma and find co-expression of both proteins in murine pancreatic ?-cells. We further demonstrate that hK7 cleaves human insulin in the A- and B-chain. Vaspin treatment of isolated pancreatic islets leads to increased insulin concentration in the media upon glucose stimulation without influencing insulin secretion. By application of vaspin and generated inactive mutants, we find the significantly improved glucose tolerance in C57BL/6NTac and db/db mice treated with recombinant vaspin fully dependent on the vaspin serpin activity and not related to vaspin-mediated changes in insulin sensitivity as determined by euglycemic-hyperinsulinemic clamp studies. Improved glucose metabolism could be mediated by increased insulin plasma concentrations 150 min after a glucose challenge in db/db mice, supporting the hypothesis that vaspin may inhibit insulin degradation by hK7 in the circulation. In conclusion, we demonstrate the inhibitory serpin nature and the first protease target of the adipose tissue-derived serpin vaspin, and our findings suggest hK7 inhibition by vaspin as an underlying physiological mechanism for its compensatory actions on obesity-induced insulin resistance.
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Serum levels of acylcarnitines are altered in prediabetic conditions.
PLoS ONE
PUBLISHED: 01-01-2013
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The role of mitochondrial function in the complex pathogenesis of type 2 diabetes is not yet completely understood. Therefore, the aim of this study was to investigate serum concentrations of short-, medium- and long-chain acylcarnitines as markers of mitochondrial function in volunteers with normal, impaired or diabetic glucose control.
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TAS2R38 and Its Influence on Smoking Behavior and Glucose Homeostasis in the German Sorbs.
PLoS ONE
PUBLISHED: 01-01-2013
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Genetic variants within the bitter taste receptor gene TAS2R38 are associated with sensitivity to bitter taste and are related to eating behavior in the Amish population. Sensitivity to bitter taste is further related to anthropometric traits in an genetically isolated Italian population. We tested whether the TAS2R38 variants (rs713598; rs1726866 and rs10246939) may be related to eating behavior, anthropometric parameters, metabolic traits and consumer goods intake in the German Sorbs.
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Common genetic variation near MC4R has a sex-specific impact on human brain structure and eating behavior.
PLoS ONE
PUBLISHED: 01-01-2013
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Obesity is associated with genetic and environmental factors but the underlying mechanisms remain poorly understood. Recent genome-wide association studies (GWAS) identified obesity- and type 2 diabetes-associated genetic variants located within or near genes that modulate brain activity and development. Among the top hits is rs17782313 near MC4R, encoding for the melanocortin-4-receptor, which is expressed in brain regions that regulate eating. Here, we hypothesized rs17782313-associated changes in human brain regions that regulate eating behavior. Therefore, we examined effects of common variants at rs17782313 near MC4R on brain structure and eating behavior. Only in female homozygous carriers of the risk allele we found significant increases of gray matter volume (GMV) in the right amygdala, a region known to influence eating behavior, and the right hippocampus, a structure crucial for memory formation and learning. Further, we found bilateral increases in medial orbitofrontal cortex, a multimodal brain structure encoding the subjective value of reinforcers, and bilateral prefrontal cortex, a higher order regulation area. There was no association between rs17782313 and brain structure in men. Moreover, among female subjects only, we observed a significant increase of disinhibition, and, more specifically, on emotional eating scores of the Three Factor Eating Questionnaire in carriers of the variant rs17782313s risk allele. These findings suggest that rs17782313s effect on eating behavior is mediated by central mechanisms and that these effects are sex-specific.
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Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans.
J. Endocrinol.
PUBLISHED: 01-01-2013
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Rather than a traditional growth factor, fibroblast growth factor-21 (FGF21) is considered to be a metabolic hormone. In the current study, we investigated serum FGF21 levels in the self-contained population of Sorbs. Serum FGF21 concentrations were quantified by ELISA and correlated with IGF1 as well as metabolic, renal, hepatic, inflammatory, and cardiovascular parameters in 913 Sorbs from Germany. Moreover, human IGF1 protein secretion was investigated in FGF21-stimulated HepG2 cells. Median FGF21 serum concentrations were 2.1-fold higher in subjects with type 2 diabetes mellitus (141.8?ng/l) compared with controls (66.7?ng/l). Furthermore, nondiabetic subjects with FGF21 levels below the detection limit of the ELISA showed a more beneficial metabolic profile compared with subjects with measurable FGF21. Moreover, FGF21 was significantly lower in female compared with male subjects after adjustment for age and BMI. In multiple regression analyses, circulating FGF21 concentrations remained independently and positively associated with gender, systolic blood pressure, triglycerides, and ? glutamyl transferase whereas a negative association was observed with IGF1 in nondiabetic subjects. Notably, FGF21 significantly inhibited IGF1 secretion into HepG2 cell culture supernatants in preliminary in vitro experiments. FGF21 serum concentrations are associated with facets of the metabolic syndrome, hepatocellular function, as well as GH status.
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C57BL/6JRj mice are protected against diet induced obesity (DIO).
Biochem. Biophys. Res. Commun.
PUBLISHED: 11-29-2011
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The C57BL/6 (B6) is one of the oldest inbred mouse strains. It has been widely used as control strain in metabolism research for many decades. Preliminary data from our lab indicated that C57BL/6JRj mice are not responding to diet induced obesity. Therefore, the aim of this study was to compare the two different B6 substrains, C57BL/6NTac and C57BL/6JRj, in regard to their response to diet induced obesity (DIO) and to investigate genetic differences which may explain such phenotypic differences. Sixteen male mice of C57BL/6NTac and C57BL/6JRj were fed a high fat diet (HFD) or standard chow diet (SD) for 10 weeks. Phenotypic characterization included measurements of bodyweight, physical activity, food intake and relative epigonadal fat mass. Genetic differences between both substrains were analyzed using a panel of 1449 single nucleotide polymorphism (SNP) markers. Our study revealed that C57BL/6JRj mice are protected against DIO independently from food intake and physical activity. Genetic SNP analysis among C57BL/6 mice identified genetic differences in at least 11 SNPs. Our data strongly support the importance of attention on the genetic background in obesity research.
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Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts.
BMC Med. Genet.
PUBLISHED: 11-17-2011
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Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans.
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New gene functions in megakaryopoiesis and platelet formation.
Christian Gieger, Aparna Radhakrishnan, Ana Cvejic, Weihong Tang, Eleonora Porcu, Giorgio Pistis, Jovana Serbanovic-Canic, Ulrich Elling, Alison H Goodall, Yann Labrune, Lorna M Lopez, Reedik Mägi, Stuart Meacham, Yukinori Okada, Nicola Pirastu, Rossella Sorice, Alexander Teumer, Katrin Voss, Weihua Zhang, Ramiro Ramirez-Solis, Joshua C Bis, David Ellinghaus, Martin Gögele, Jouke-Jan Hottenga, Claudia Langenberg, Peter Kovacs, Paul F O'Reilly, So-Youn Shin, Tonu Esko, Jaana Hartiala, Stavroula Kanoni, Federico Murgia, Afshin Parsa, Jonathan Stephens, Pim van der Harst, C Ellen van der Schoot, Hooman Allayee, Antony Attwood, Beverley Balkau, François Bastardot, Saonli Basu, Sebastian E Baumeister, Ginevra Biino, Lorenzo Bomba, Amélie Bonnefond, Francois Cambien, John C Chambers, Francesco Cucca, Pio D'Adamo, Gail Davies, Rudolf A de Boer, Eco J C de Geus, Angela Döring, Paul Elliott, Jeanette Erdmann, David M Evans, Mario Falchi, Wei Feng, Aaron R Folsom, Ian H Frazer, Quince D Gibson, Nicole L Glazer, Chris Hammond, Anna-Liisa Hartikainen, Susan R Heckbert, Christian Hengstenberg, Micha Hersch, Thomas Illig, Ruth J F Loos, Jennifer Jolley, Kay Tee Khaw, Brigitte Kühnel, Marie-Christine Kyrtsonis, Vasiliki Lagou, Heather Lloyd-Jones, Thomas Lumley, Massimo Mangino, Andrea Maschio, Irene Mateo Leach, Barbara McKnight, Yasin Memari, Braxton D Mitchell, Grant W Montgomery, Yusuke Nakamura, Matthias Nauck, Gerjan Navis, Ute Nöthlings, Ilja M Nolte, David J Porteous, Anneli Pouta, Peter P Pramstaller, Janne Pullat, Susan M Ring, Jerome I Rotter, Daniela Ruggiero, Aimo Ruokonen, Cinzia Sala, Nilesh J Samani, Jennifer Sambrook, David Schlessinger, Stefan Schreiber, Heribert Schunkert, James Scott, Nicholas L Smith, Harold Snieder, John M Starr, Michael Stumvoll, Atsushi Takahashi, W H Wilson Tang, Kent Taylor, Albert Tenesa, Swee Lay Thein, Anke Tönjes, Manuela Uda, Sheila Ulivi, Dirk J van Veldhuisen, Peter M Visscher, Uwe Völker, H-Erich Wichmann, Kerri L Wiggins, Gonneke Willemsen, Tsun-Po Yang, Jing Hua Zhao, Paavo Zitting, John R Bradley, George V Dedoussis, Paolo Gasparini, Stanley L Hazen, Andres Metspalu, Mario Pirastu, Alan R Shuldiner, L Joost van Pelt, Jaap-Jan Zwaginga, Dorret I Boomsma, Ian J Deary, Andre Franke, Philippe Froguel, Santhi K Ganesh, Marjo-Riitta Järvelin, Nicholas G Martin, Christa Meisinger, Bruce M Psaty, Timothy D Spector, Nicholas J Wareham, Jan-Willem N Akkerman, Marina Ciullo, Panos Deloukas, Andreas Greinacher, Steve Jupe, Naoyuki Kamatani, Jyoti Khadake, Jaspal S Kooner, Josef Penninger, Inga Prokopenko, Derek Stemple, Daniela Toniolo, Lorenz Wernisch, Serena Sanna, Andrew A Hicks, Augusto Rendon, Manuel A Ferreira, Willem H Ouwehand, Nicole Soranzo.
Nature
PUBLISHED: 10-21-2011
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Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
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Reduced food intake and body weight in mice deficient for the G protein-coupled receptor GPR82.
PLoS ONE
PUBLISHED: 09-16-2011
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G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments.
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Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes.
J. Proteome Res.
PUBLISHED: 08-29-2011
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Obesity is associated with multiple adverse health effects and a high risk of developing metabolic and cardiovascular diseases. Therefore, there is a great need to identify circulating parameters that link changes in body fat mass with obesity. This study combines proteomic and metabolomic approaches to identify circulating molecules that discriminate healthy lean from healthy obese individuals in an exploratory study design. To correct for variations in physical activity, study participants performed a one hour exercise bout to exhaustion. Subsequently, circulating factors differing between lean and obese individuals, independent of physical activity, were identified. The DIGE approach yielded 126 differentially abundant spots representing 39 unique proteins. Differential abundance of proteins was confirmed by ELISA for antithrombin-III, clusterin, complement C3 and complement C3b, pigment epithelium-derived factor (PEDF), retinol binding protein 4 (RBP4), serum amyloid P (SAP), and vitamin-D binding protein (VDBP). Targeted serum metabolomics of 163 metabolites identified 12 metabolites significantly related to obesity. Among those, glycine (GLY), glutamine (GLN), and glycero-phosphatidylcholine 42:0 (PCaa 42:0) serum concentrations were higher, whereas PCaa 32:0, PCaa 32:1, and PCaa 40:5 were decreased in obese compared to lean individuals. The integrated bioinformatic evaluation of proteome and metabolome data yielded an improved group separation score of 2.65 in contrast to 2.02 and 2.16 for the single-type use of proteomic or metabolomics data, respectively. The identified circulating parameters were further investigated in an extended set of 30 volunteers and in the context of two intervention studies. Those included 14 obese patients who had undergone sleeve gastrectomy and 12 patients on a hypocaloric diet. For determining the long-term adaptation process the samples were taken six months after the treatment. In multivariate regression analyses, SAP, CLU, RBP4, PEDF, GLN, and C18:2 showed the strongest correlation to changes in body fat mass. The combined serum proteomic and metabolomic profiling reveals a link between the complement system and obesity and identifies both novel (C3b, CLU, VDBP, and all metabolites) and confirms previously discovered markers (PEDF, RBP4, C3, ATIII, and SAP) of body fat mass changes.
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Role of genetic variation in the human sodium-glucose cotransporter 2 gene (SGLT2) in glucose homeostasis.
Pharmacogenomics
PUBLISHED: 08-10-2011
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Mutations in the sodium-glucose cotransporter 2 (SGLT2), as well as treatment with SGLT2 inhibitors result in reduced fasting glucose levels, HbA(1c) and BMI. We therefore investigated the effects of common genetic variation in SGLT2 on human Type 2 diabetes and related traits.
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Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity.
Eur. J. Hum. Genet.
PUBLISHED: 05-11-2011
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Population isolates have long been of interest to genetic epidemiologists because of their potential to increase power to detect disease-causing genetic variants. The Sorbs of Germany are considered as cultural and linguistic isolates and have recently been the focus of disease association mapping efforts. They are thought to have settled in their present location in eastern Germany after a westward migration from a largely Slavic-speaking territory during the Middle Ages. To examine Sorbian genetic diversity within the context of other European populations, we analyzed genotype data for over 30?000 autosomal single-nucleotide polymorphisms from over 200 Sorbs individuals. We compare the Sorbs with other European individuals, including samples from population isolates. Despite their geographical proximity to German speakers, the Sorbs showed greatest genetic similarity to Polish and Czech individuals, consistent with the linguistic proximity of Sorbian to other West Slavic languages. The Sorbs also showed evidence of subtle levels of genetic isolation in comparison with samples from non-isolated European populations. The level of genetic isolation was less than that observed for the Sardinians and French Basque, who were clear outliers on multiple measures of isolation. The finding of the Sorbs as only a minor genetic isolate demonstrates the need to genetically characterize putative population isolates, as they possess a wide range of levels of isolation because of their different demographic histories.
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[The use of PET/CT in radiotherapy of patients with non-small cell lung cancer].
Magy Onkol
PUBLISHED: 04-26-2011
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The goal of this paper was to investigate the influence of FDG-PET/CT scan on the modification of staging and irradiation planning in patients suffering from non-small cell lung cancer (NSCLC). Fifteen patients suffering from NSCLC were analyzed by the authors from January, 2008 to July, 2009. The aim of the analysis was to examine the influence of FDG-PET/CT on irradiation planning and on decision-making of the complex oncologic therapy. The FDG-PET/CT scan was carried out in the position of irradiation performed later. For irradiation planning, planning target volumes (PTV) and the organs of risk were contoured on the patients topometric CT slides as well as on the fused FDG-PET/CT slides. We evaluated how the application of PET/CT modified the stage of the illness, the complex oncologic therapeutic plan, the volume and the localization of the PTV, and the irradiation doses of the organs at risk. The mean and maximum dose of the spinal cord, the mean and V20 dose load of the lungs and the mean dose loads of the heart as well as of the left ventricle were measured. In 8 of 15 cases the stage of the disease and the treatment strategy was modified, since distant metastases were detected by the PET/CT. We evaluated the modification of the PTV and dose load of the organs at risk in 7 cases. According to the PET/CT the PTV was reduced in 5 cases (mean: 393.6 cm3) and was increased in 2 cases (mean: 250.8 cm3). Concerning the risk organs we found that the average (8.8 Gy/9.5 Gy) and maximum (33.4 Gy/36.4 Gy) dose load of the spinal cord increased, while the average (24.5 Gy/13.8 Gy) and V20 (33.7%/22.1%) dose load of the lungs decreased. We likewise found a decrease in the mean dose load of the heart (17.3 Gy/16.8 Gy) and left ventricle (12.9 Gy/9.6 Gy). In the majority of the cases the FDG-PET/CT scan modified the therapeutic decision, the size of the irradiated volume, and the dose load of the lung, the organ at risk causing the most difficulties at irradiation planning, was also reduced. The PET/CT scan plays an essential role in the complex oncologic treatment and irradiation therapy of NSCLC.
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The effect of ACACB cis-variants on gene expression and metabolic traits.
PLoS ONE
PUBLISHED: 04-01-2011
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Acetyl Coenzyme A carboxylase ? (ACACB) is the rate-limiting enzyme in fatty acid oxidation, and continuous fatty acid oxidation in Acacb knock-out mice increases insulin sensitivity. Systematic human studies have not been performed to evaluate whether ACACB variants regulate gene expression and insulin sensitivity in skeletal muscle and adipose tissues. We sought to determine whether ACACB transcribed variants were associated with ACACB gene expression and insulin sensitivity in non-diabetic African American (AA) and European American (EA) adults.
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Population-genetic comparison of the Sorbian isolate population in Germany with the German KORA population using genome-wide SNP arrays.
BMC Genet.
PUBLISHED: 03-14-2011
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The Sorbs are an ethnic minority in Germany with putative genetic isolation, making the population interesting for disease mapping. A sample of N = 977 Sorbs is currently analysed in several genome-wide meta-analyses. Since genetic differences between populations are a major confounding factor in genetic meta-analyses, we compare the Sorbs with the German outbred population of the KORA F3 study (N = 1644) and other publically available European HapMap populations by population genetic means. We also aim to separate effects of over-sampling of families in the Sorbs sample from effects of genetic isolation and compare the power of genetic association studies between the samples.
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Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption.
Hum. Mol. Genet.
PUBLISHED: 02-28-2011
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Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), The Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10(-14)) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10(-11)). An effect of ?0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.
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TCF7L2 and therapeutic response to sulfonylureas in patients with type 2 diabetes.
BMC Med. Genet.
PUBLISHED: 02-24-2011
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Variants in the TCF7L2 have been shown to be associated with an increased risk for type 2 diabetes (T2D). Since the association with diabetes could be explained by effects on insulin secretion, we investigated whether patients with diabetes risk alleles at rs7903146 might have an altered hypoglycaemic response to sulfonylureas (SUs).
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[Modern three-dimensional conformal craniospinal radiotherapy].
Magy Onkol
PUBLISHED: 02-15-2011
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The main problem of craniospinal irradiation (CSI) is the matching of the fields. The use of a suitable technique is very important because matching of the fields is necessary to use for the optimal cancer irradiation of the long planning target volume (PTV). Since 2007, 8 patients have received CT-based, 3D-planned conformal CSI in our Institute. Patient immobilization was made in prone position in a vacuum bed, using skull and pelvis masks. Organ-at-risk (OAR) contours were made by radiographers. PTV was contoured by radiation oncologists. The prescribed dose to the PTV was 36 Gy with 1.8 Gy dose per fraction. In the planning process the following aspects were taken under consideration: all points of the PTV had to receive at least 95% of the prescribed dose (according to ICRU 50, 62); at junction field edges the overlapping parts were eliminated using a multisegmental technique, where the adjacent segment ends of the neighbouring fields were shifted two times 2 cm, so that the three equally weighted segments used in one field had 2-2 cm distance from each other. In the CSI planning the shape of the patient and so the length of the PTV has made a big emphasis on determining the number of field matching. Thus in some cases instead of two, only one field matching was sufficient - this could be achieved by increasing the source-to-skin distance (SSD) of the fields. The verification made with a solid-water phantom justified the precision of the field matching. The offset used at junction field edges in between one treatment facilitates the verification of field matching - and so the patient positioning. Thus the possibility of having overdosed regions could be reduced, which was very important from a radiation biological point of view.
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Genetic and evolutionary analyses of the human bone morphogenetic protein receptor 2 (BMPR2) in the pathophysiology of obesity.
PLoS ONE
PUBLISHED: 02-02-2011
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Human bone morphogenetic protein receptor 2 (BMPR2) is essential for BMP signalling and may be involved in the regulation of adipogenesis. The BMPR2 locus has been suggested as target of recent selection in human populations. We hypothesized that BMPR2 might have a role in the pathophysiology of obesity.
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Insulin resistance occurs in parallel with sensory neuropathy in streptozotocin-induced diabetes in rats: differential response to early vs late insulin supplementation.
Metab. Clin. Exp.
PUBLISHED: 01-26-2011
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We investigated whether progressive sensory neuropathy was accompanied by changes in whole-body insulin sensitivity (WBIS) in rats made diabetic by streptozotocin (STZ). The effects of early and late insulin supplementation were also studied. The STZ-treated rats failed to gain weight and exhibited stable hyperglycemia and low plasma insulin levels with a decrease in nerve conduction velocity (NCV) measured in A and C fibers of the saphenous nerve. A decreased sensory neuropeptide (SNP) release such as that of substance P, somatostatin, and calcitonin gene-related peptide determined from organ fluid of tracheal preparations subjected to electrical field stimulation also occurred in diabetic animals. These features were accompanied by a decrease in WBIS measured by hyperinsulinemic-euglycemic glucose clamping and a decrease in insulin-stimulated glucose uptake in cardiac and gastrocnemius muscle. When insulin supplementation with slow-release implants (2 IU/d) was started 4 weeks after STZ injection, blood glucose level normalized. Both insulin sensitivity and sensory nerve function reflected in either NCV or SNP release completely recovered by the 12th post-STZ week. When the insulin implants were applied from the eighth post-STZ week, both WBIS and glucose uptake remained significantly decreased, with a seriously impaired NCV and SNP release with strong hyperglycemia. Late insulin supplementation, however, even by using double implantation from the 10th post-STZ week, was unable to restore blood glucose, WBIS, NCV, and SNP release by the 12th week. Insulin resistance occurs in parallel with sensory neuropathy in STZ-diabetic rats. Both can be improved by early but not late insulin supplementation.
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Impact of clinical factors and CYP2C9 variants for the risk of severe sulfonylurea-induced hypoglycemia.
Eur. J. Clin. Pharmacol.
PUBLISHED: 01-07-2011
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The established risk factors for severe sulfonylurea-induced hypoglycemia (SH) include low hemoglobin (Hb)A(1c), advanced age, long duration of diabetes, multimorbidity, and polypharmacy. As the genetically polymorphic cytochrome P450 (CYP), enzyme CYP2C9 is mainly responsible for the hepatic metabolism of sulfonylureas (SUs), we hypothesized that the slow-metabolizer genotypes *2/*2, *2/*3, and *3/*3 might be overrepresented in type 2 diabetic patients with SH.
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[Conformal stereotactic radiosurgery therapy: plan evaluation methods and results].
Magy Onkol
PUBLISHED: 01-06-2011
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The purpose of our study was the objective evaluation of micro-multileaf collimator (mMLC)-based stereotactic radiosurgery treatment plans. Forty-seven patients, 71 lesions received static beam conformal stereotactic radiosurgery treatment in our institute between November 2005 and June 2008. Target volume and organs at risk were outlined on a MRI-CT image fusion basis. BrainSCAN 5.31 system (BrainLAB AG, Heimstetten, Germany) was used for treatment planning, Elekta Presice TS linear accelerator (Elekta Oncology Systems Ltd, Crawley, UK) and BrainLAB m3 mMLC were used for treatment delivery. An invasive head frame, mounted to the treatment table, was used with four screws for patient head fixation. Treatment plans were analysed with objective parameters, such as conformal index (COIN), homogeneity index (HI), coverage index (CI) and healthy tissue relative overdose factor (HTOF) tools. x2 tests were performed between COIN, HI and the geometrical parameters of the target volume (lesion volume - LV, lesion-organ distance - LOD, lesion deformity index - LDI). Mean value of COIN, HI, HTOF and CI was 0.52 (SD 0.13), 1.16 (SD 0.1), 0.88 (SD 0.53), and 0.94 (SD 0.11), respectively. COIN significantly correlated with (p<0.001 in all three cases), while HI was independent of LV, LOD, LDI (p=0.94; 0.14 and 0.72). COIN is similar, HTOF is less than data from the literature. According to our results geometrical parameters of the target volume (size, location, deformation) significantly influence the COIN, but they have no effect on HI.
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Effects of genetic variants in ADCY5, GIPR, GCKR and VPS13C on early impairment of glucose and insulin metabolism in children.
PLoS ONE
PUBLISHED: 01-05-2011
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Recent genome-wide association studies identified novel candidate genes for fasting and 2 h blood glucose and insulin levels in adults. We investigated the role of four of these loci (ADCY5, GIPR, GCKR and VPS13C) in early impairment of glucose and insulin metabolism in children.
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Targeted SNP genotyping using the TaqMan® assay.
Methods Mol. Biol.
PUBLISHED: 01-05-2011
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More than 99% of genomic DNA sequence is identical among humans, and not surprisingly, slight variations in sequence can often produce a major effect on phenotype. Sequence variants may also mediate the manner in which humans are susceptible to disease or respond to environmental factors such as bacteria, viruses, toxins, chemicals, drugs, and therapeutic interventions. Single-nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single base in the genome sequence can be represented by at least two different nucleotides. In the last decade, numerous SNPs have been identified that explain, at least partially, the genetic architecture of complex diseases such as cancer, diabetes, vascular complications, some forms of mental illness, and a multitude of other disorders. Disease-related SNPs are commonly identified through candidate gene approaches, or more recently, through genome-wide association studies. In either case, findings of association require verification in independent, population-based, study samples, usually consisting of several hundreds/thousands of individuals. A convenient technique to genotype a moderate number of markers in this kind of study is available with the TaqMan® platform (Applied Biosystems; Foster City, CA), which utilizes polymerase chain reaction amplification and allelic discrimination to easily and efficiently generate genotype data in a cost-effective way. Here, we introduce and describe this commonly used technique and include protocols that can be directly used in laboratories aiming to perform moderate- to large-scale genotyping studies.
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Embryo selection or uterine environment: which plays the greater role in blastocyst transfer cycles?
J. Obstet. Gynaecol. Res.
PUBLISHED: 11-28-2010
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Blastocyst stage embryo transfer (BET) leads to higher pregnancy rates when compared to cleavage stage transfer. Better embryo selection and a more physiologic stage of transfer are possible explanations. We assessed the significance of embryo selection in achieving an improved outcome.
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Serum vaspin concentrations are decreased after exercise-induced oxidative stress.
Obes Facts
PUBLISHED: 10-20-2010
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Elevated visceral adipose tissue-derived serpin (vaspin) serum concentrations are associated with impaired insulin sensitivity, but increase unexpectedly after long-term physical training. We therefore investigated the effect of an acute exercise bout and the effects of vitamin supplementation on chronic exercise effect and on serum vaspin concentrations. We measured serum vaspin and thiobarbituric acid-reactive substances (TBARS) concentrations in 80 individuals before and after a 1-hour acute exercise bout and independently in 40 healthy young men who were randomly assigned to either antioxidant (vitamin C (1,000 mg/day) and vitamin E (400 IU/day)) or to no supplementation after a standardized 4-week physical training program as a post hoc analysis. Serum vaspin concentrations significantly decreased after acute physical exercise as well as after 4 weeks of training in individuals without antioxidants. Changes in vaspin serum concentration correlate with increased TBARS serum concentrations both in response to a 1-hour exercise bout (r = -0.42, p < 0.01) and to the 4-week training (r = -0.31, p < 0.05). Interestingly, supplementation with antioxidants rather increased circulating vaspin levels in response to 4 weeks of exercise. In conclusion, vaspin serum concentrations are decreased by exercise-induced oxidative stress, but not by exercise-associated improvement in insulin sensitivity.
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Common variants at 10 genomic loci influence hemoglobin A?(C) levels via glycemic and nonglycemic pathways.
Nicole Soranzo, Serena Sanna, Eleanor Wheeler, Christian Gieger, Dörte Radke, Josée Dupuis, Nabila Bouatia-Naji, Claudia Langenberg, Inga Prokopenko, Elliot Stolerman, Manjinder S Sandhu, Matthew M Heeney, Joseph M Devaney, Muredach P Reilly, Sally L Ricketts, Alexandre F R Stewart, Benjamin F Voight, Christina Willenborg, Benjamin Wright, David Altshuler, Dan Arking, Beverley Balkau, Daniel Barnes, Eric Boerwinkle, Bernhard Böhm, Amélie Bonnefond, Lori L Bonnycastle, Dorret I Boomsma, Stefan R Bornstein, Yvonne Böttcher, Suzannah Bumpstead, Mary Susan Burnett-Miller, Harry Campbell, Antonio Cao, John Chambers, Robert Clark, Francis S Collins, Josef Coresh, Eco J C de Geus, Mariano Dei, Panos Deloukas, Angela Döring, Josephine M Egan, Roberto Elosua, Luigi Ferrucci, Nita Forouhi, Caroline S Fox, Christopher Franklin, Maria Grazia Franzosi, Sophie Gallina, Anuj Goel, Jurgen Graessler, Harald Grallert, Andreas Greinacher, David Hadley, Alistair Hall, Anders Hamsten, Caroline Hayward, Simon Heath, Christian Herder, Georg Homuth, Jouke-Jan Hottenga, Rachel Hunter-Merrill, Thomas Illig, Anne U Jackson, Antti Jula, Marcus Kleber, Christopher W Knouff, Augustine Kong, Jaspal Kooner, Anna Köttgen, Peter Kovacs, Knut Krohn, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Mark Lathrop, Cécile Lecoeur, Man Li, Mingyao Li, Ruth J F Loos, Jian'an Luan, Valeriya Lyssenko, Reedik Mägi, Patrik K E Magnusson, Anders Malarstig, Massimo Mangino, María Teresa Martínez-Larrad, Winfried März, Wendy L McArdle, Ruth McPherson, Christa Meisinger, Thomas Meitinger, Olle Melander, Karen L Mohlke, Vincent E Mooser, Mario A Morken, Narisu Narisu, David M Nathan, Matthias Nauck, Chris O'Donnell, Konrad Oexle, Nazario Olla, James S Pankow, Felicity Payne, John F Peden, Nancy L Pedersen, Leena Peltonen, Markus Perola, Ozren Polašek, Eleonora Porcu, Daniel J Rader, Wolfgang Rathmann, Samuli Ripatti, Ghislain Rocheleau, Michael Roden, Igor Rudan, Veikko Salomaa, Richa Saxena, David Schlessinger, Heribert Schunkert, Peter Schwarz, Udo Seedorf, Elizabeth Selvin, Manuel Serrano-Ríos, Peter Shrader, Angela Silveira, David Siscovick, Kjioung Song, Timothy D Spector, Kari Stefansson, Valgerdur Steinthorsdottir, David P Strachan, Rona Strawbridge, Michael Stumvoll, Ida Surakka, Amy J Swift, Toshiko Tanaka, Alexander Teumer, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Anke Tönjes, Gianluca Usala, Veronique Vitart, Henry Völzke, Henri Wallaschofski, Dawn M Waterworth, Hugh Watkins, H-Erich Wichmann, Sarah H Wild, Gonneke Willemsen, Gordon H Williams, James F Wilson, Juliane Winkelmann, Alan F Wright, , Carina Zabena, Jing Hua Zhao, Stephen E Epstein, Jeanette Erdmann, Hakon H Hakonarson, Sekar Kathiresan, Kay-Tee Khaw, Robert Roberts, Nilesh J Samani, Mark D Fleming, Robert Sladek, Goncalo Abecasis, Michael Boehnke, Philippe Froguel, Leif Groop, Mark I McCarthy, W H Linda Kao, Jose C Florez, Manuela Uda, Nicholas J Wareham, Inês Barroso, James B Meigs.
Diabetes
PUBLISHED: 09-21-2010
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Glycated hemoglobin (HbA?(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA?(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA?(c) levels.
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Evaluation of A2BP1 as an obesity gene.
Diabetes
PUBLISHED: 08-19-2010
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A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity.
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Repin1 maybe involved in the regulation of cell size and glucose transport in adipocytes.
Biochem. Biophys. Res. Commun.
PUBLISHED: 08-13-2010
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Replication initiator 1 (Repin1) is highly expressed in liver and adipose tissue and has been suggested as candidate gene for obesity and its related metabolic disorders in congenic and subcongenic rat strains. The cellular localization and function of Repin1 has remained elusive since its discovery in 1990. To characterize the role of Repin1 in adipocyte biology, we used siRNA knockdown technology to reduce the expression of Repin1 by electroporation of semiconfluent 3T3-L1 preadipocytes. Glucose transport, palmitate uptake as well as triglyceride content were measured. In paired samples of human visceral and subcutaneous adipose tissue, we investigated whether Repin1 mRNA expression is related to measures of fat accumulation and adipocyte size. We demonstrate that Repin1 increases during adipogenesis. RNA interference based Repin1 downregulation in mature adipocytes significantly reduces adipocyte size and causes reduced basal, but enhanced insulin stimulated glucose uptake into 3T3-L1 cells. Additionally, knockdown of Repin1 resulted in reduced palmitate uptake and significantly changed the mRNA expression of genes involved lipid droplet formation, adipogenesis, glucose and fatty acid transport. Furthermore, we found significant correlations between Repin1 mRNA expression in human paired visceral and subcutaneous adipose tissue and total body fat mass as well as adipocyte size. We have identified a potential role for Repin1 in the regulation of adipocyte size and expression of glucose transporters GLUT1 and GLUT4 in adipocytes.
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Gastric bypass surgery alters behavioral and neural taste functions for sweet taste in obese rats.
Am. J. Physiol. Gastrointest. Liver Physiol.
PUBLISHED: 07-15-2010
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Roux-en-Y gastric bypass surgery (GBS) is the most effective treatment for morbid obesity. GBS is a restrictive malabsorptive procedure, but many patients also report altered taste preferences. This study investigated the effects of GBS or a sham operation (SH) on body weight, glucose tolerance, and behavioral and neuronal taste functions in the obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-1 receptors and lean controls (LETO). OLETF-GBS rats lost body weight (-26%) and demonstrated improved glucose tolerance. They also expressed a reduction in 24-h two-bottle preference for sucrose (0.3 and 1.0 M) and decreased 10-s lick responses for sucrose (0.3 through 1.5 M) compared with OLETF-SH or LETO-GBS. A similar effect was noted for other sweet compounds but not for salty, sour, or bitter tastants. In lean rats, GBS did not alter responses to any stimulus tested. Extracellular recordings from 170 taste-responsive neurons of the pontine parabrachial nucleus revealed a rightward shift in concentration responses to oral sucrose in obese compared with lean rats (OLETF-SH vs. LETO-SH): overall increased response magnitudes (above 0.9 M), and maximum responses occurring at higher concentrations (+0.46 M). These effects were reversed by GBS, and neural responses in OLETF-GBS were statistically not different from those in any LETO groups. These findings confirm obesity-related alterations in taste functions and demonstrate the ability of GBS to alleviate these impairments. Furthermore, the beneficial effects of GBS appear to be independent of CCK-1 receptor signaling. An understanding of the underlying mechanisms for reduced preferences for sweet taste could help in developing less invasive treatments for obesity.
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Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.
PLoS Genet.
PUBLISHED: 06-24-2010
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Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p?=?3.20×10(-111)) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p?=?1.22×10(-11)) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins.
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Insulin-sensitive obesity.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 06-22-2010
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The association between obesity and impaired insulin sensitivity has long been recognized, although a subgroup of obese individuals seems to be protected from insulin resistance. In this study, we systematically studied differences in adipose tissue biology between insulin-sensitive (IS) and insulin-resistant (IR) individuals with morbid obesity. On the basis of glucose infusion rate during euglycemic hyperinsulinemic clamps, 60 individuals with a BMI of 45 +/- 1.3 kg/m(2) were divided into an IS and IR group matched for age, sex, and body fat prior to elective surgery. We measured fat distribution, circulating adipokines, and parameters of inflammation, glucose, and lipid metabolism and characterized adipose tissue morphology, function, and mRNA expression in abdominal subcutaneous (sc) and omental fat. IS compared with IR obese individuals have significantly lower visceral fat area (138 +/- 27 vs. 316 +/- 91 cm(2)), number of macrophages in omental adipose tissue (4.9 +/- 0.8 vs. 13.2 +/- 1.4%), mean omental adipocyte size (528 +/- 76 vs. 715 +/- 81 pl), circulating C-reactive protein, progranulin, chemerin, and retinol-binding protein-4 (all P values <0.05), and higher serum adiponectin (6.9 +/- 3.4 vs. 3.4 +/- 1.7 ng/ml) and omental adipocyte insulin sensitivity (all P values <0.01). The strongest predictors of insulin sensitivity by far were macrophage infiltration together with circulating adiponectin (r(2) = 0.98, P < 0.0001). In conclusion, independently of total body fat mass, increased visceral fat accumulation and adipose tissue dysfunction are associated with IR obesity. This suggests that mechanisms beyond a positive caloric balance such as inflammation and adipokine release determine the pathological metabolic consequences in patients with obesity.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.