المؤلفون: Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josee Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Procardis Consortium, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, MAGIC investigators, GLGC Consortium, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Pare, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Åsa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena Gonzalez, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, Jose M Ordovas, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Sekar Kathiresan

المصدر: PLoS Genetics, Vol 8, Iss 3, p e1002607 (2012)

مصطلحات موضوعية: Genetics, QH426-470

الوصف: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

وصف الملف: electronic resource

العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22479202/?tool=EBITest; https://doaj.org/toc/1553-7390Test; https://doaj.org/toc/1553-7404Test

الوصول الحر: https://doaj.org/article/d72a07536f4c468e8ab94500a1e663a5Test

المؤلفون: Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, DIAGRAM Consortium, MAGIC Investigators, Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michele M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek

المصدر: PLoS ONE, Vol 7, Iss 1, p e29202 (2012)

مصطلحات موضوعية: Medicine, Science

الوصف: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3251563?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/73ab7f9637a040a28be2840650771705Test

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

المصدر: PLoS Genetics, Vol 5, Iss 6, p e1000508 (2009)

مصطلحات موضوعية: Genetics, QH426-470

الوصف: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

وصف الملف: electronic resource

العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19557161/pdf/?tool=EBITest; https://doaj.org/toc/1553-7390Test; https://doaj.org/toc/1553-7404Test

الوصول الحر: https://doaj.org/article/53eb782f29cd4abcb81556de526eb32fTest

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

المصدر: PLoS Genetics, Vol 5, Iss 7 (2009)

مصطلحات موضوعية: Genetics, QH426-470

العلاقة: http://europepmc.org/articles/PMC2722420Test; https://doaj.org/toc/1553-7390Test; https://doaj.org/toc/1553-7404Test; https://doaj.org/article/e44f8db0afa249ddb81fb6414958ef65Test

الإتاحة: https://doi.org/10.1371/annotation/b6e8f9f6-2496-4a40-b0e3-e1d1390c1928Test
https://doaj.org/article/e44f8db0afa249ddb81fb6414958ef65Test

المؤلفون: Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L Mcardle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordströ, Peter Nordströ, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renströ, Aimo 50, Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M Van Duijn, Nicholas J Wareham, Hugh Watkins For The Procardis Consortia, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H.-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke

المساهمون: The Pennsylvania State University CiteSeerX Archives

المصدر: http://csg.sph.umich.edu/boehnke/pdf/plosg-e1000508.pdfTest.

وصف الملف: application/pdf

العلاقة: http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.1050.2092Test; http://csg.sph.umich.edu/boehnke/pdf/plosg-e1000508.pdfTest

الإتاحة: http://csg.sph.umich.edu/boehnke/pdf/plosg-e1000508.pdfTest

المؤلفون: Cristen J Willer, Serena Sanna, Anne U Jackson, Angelo Scuteri, Lori L Bonnycastle, Robert Clarke, Simon C Heath, Nicholas J Timpson, Samer S Najjar, Heather M Stringham, James Strait, William L Duren, Andrea Maschio, Fabio Busonero, Antonella Mulas, Giuseppe Albai, Amy J Swift, Mario A Morken, Narisu Narisu, Derrick Bennett, Sarah Parish, Haiqing Shen, Pilar Galan, Pierre Meneton, Serge Hercberg, Diana Zelenika, Wei-Min Chen, Yun Li, Laura J Scott, Paul A Scheet, Jouko Sundvall, Richard M Watanabe, Ramaiah Nagaraja, Shah Ebrahim, Debbie A Lawlor, Yoav Ben-Shlomo, George Davey-Smith, Alan R Shuldiner, Rory Collins, Richard N Bergman, Manuela Uda, Jaakko Tuomilehto, Antonio Cao, Francis S Collins, Edward Lakatta, G Mark Lathrop, Michael Boehnke, David Schlessinger, Karen L Mohlke, amp, Gonçalo, R Abecasis

المساهمون: The Pennsylvania State University CiteSeerX Archives

المصدر: http://csg.sph.umich.edu/abecasis/publications/pdf/Nat.Genet.vol.40-pp.161.pdfTest.

الوصف: To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls. Coronary artery disease (CAD) and stroke are the leading causes of morbidity, mortality and disability in industrialized countries, and the prevalence of these diseases is increasing rapidly in developing countries 1 . A main underlying pathology is atherosclerosis, a process of cumulative deposition of LDL cholesterol in the arteries supplying blood to the heart and brain that eventually leads to impaired or absent blood supply and myocardial infarction or stroke 1 . Consistent and compelling evidence has demonstrated association between lipoprotein-associated lipid concentrations and ...

وصف الملف: application/pdf

العلاقة: http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.1074.8480Test; http://csg.sph.umich.edu/abecasis/publications/pdf/Nat.Genet.vol.40-pp.161.pdfTest

الإتاحة: http://csg.sph.umich.edu/abecasis/publications/pdf/Nat.Genet.vol.40-pp.161.pdfTest

المؤلفون: Anne U. Jackson, Francis S. Collins, Romy Kursawe, Ryan P. Welch, Michael L. Stitzel, Brooke N. Wolford, Michael R. Erdos, Michael Boehnke, Arushi Varshney, Ying Wu, Martin L. Buchkovich, Swarooparani Vadlamudi, Stephen C. J. Parker, Laura J. Scott, Karen L. Mohlke, Grace J. Kwon, Maren E Cannon, Markku Laakso, Tamara S. Roman, Johanna Kuusisto, Mario A. Morken

المصدر: Diabetes. 66:2521-2530

مصطلحات موضوعية: 0301 basic medicine, Regulation of gene expression, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Pancreatic islets, Insulin, medicine.medical_treatment, Adenylate kinase, Type 2 diabetes, Biology, medicine.disease, Cyclase, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Internal medicine, Internal Medicine, medicine, Allele, Enhancer

الوصف: Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic β-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent β-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::aac244289bfb99d691b831b74b215ef7Test
https://doi.org/10.2337/db17-0464Test

المؤلفون: Tamara S, Roman, Maren E, Cannon, Swarooparani, Vadlamudi, Martin L, Buchkovich, Brooke N, Wolford, Ryan P, Welch, Mario A, Morken, Grace J, Kwon, Arushi, Varshney, Romy, Kursawe, Ying, Wu, Anne U, Jackson, Michael R, Erdos, Johanna, Kuusisto, Markku, Laakso, Laura J, Scott, Michael, Boehnke, Francis S, Collins, Stephen C J, Parker, Michael L, Stitzel, Karen L, Mohlke

المصدر: Diabetes

مصطلحات موضوعية: Islets of Langerhans, Diabetes Mellitus, Type 2, Gene Expression Regulation, Insulin Secretion, Genetic Variation, Humans, Insulin, Genetics/Genomes/Proteomics/Metabolomics, Adenylyl Cyclases, Genome-Wide Association Study

الوصف: Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic β-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent β-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::82c9352dae5ee296ea0429986c7fe4dfTest
https://pubmed.ncbi.nlm.nih.gov/28684635Test

المؤلفون: J. Graessler, Ulf Smith, Marie-France Hivert, Antigone S. Dimas, Joshua W. Knowles, Stéphane Cauchi, Karen L. Mohlke, Michael Boehnke, David Meyre, Nicholas J. Wareham, Ci Song, Denis Rybin, Erik Ingelsson, Mario A. Morken, Anne U. Jackson, Michael R. Erdos, Peter Kovacs, Fahim Abbasi, Claudia Langenberg, Ke Hao, Andreas Pfeiffer, Thomas Quertemous, Lars Lind, Stefan R. Bornstein, Suzannah Bumpstead, Alena Stančáková, Lori L. Bonnycastle, Michael Stumvoll, Oluf Pedersen, Themistocles L. Assimes, Inês Barroso, Andrea Benazzo, Richard M. Watanabe, Magic Investigators, Josée Dupuis, Inga Prokopenko, Heather M. Stringham, Felicity Payne, Markku Laakso, Antje Fischer-Rosinsky, Francis S. Collins, Mark Walker, James B. Meigs, Torben Hansen, Peter Schwarz, Xia Yang, Yvonne Böttcher, Hans-Ulrich Häring, Anke Tönjes, Narisu Narisu, Cécile Lecoeur, Jaakko Tuomilehto, Reedik Mägi, Joachim Spranger, Amy J. Swift, Johanna Kuusisto, Jose C. Florez, Niels Grarup, Philippe Froguel, Vasiliki Lagou, Peter S. Chines, Mark I. McCarthy, Adam Barker, Trine Welløv Boesgaard, Richard N. Bergman

المصدر: Diabetes 63, 2158-2171 (2013)
Diabetes
Diabetes, vol 63, iss 6
Dimas, A S, Lagou, V, Barker, A, Knowles, J W, Magi, R, Hivert, M F, Benazzo, A, Rybin, D, Jackson, A U, Stringham, H M, Song, C, Fischer-Rosinsky, A, Boesgaard, T W, Grarup, N, Abbasi, F A, Assimes, T L, Hao, K, Yang, X, Lecoeur, C, Barroso, I, Bonnycastle, L L, Bottcher, Y, Bumpstead, S, Chines, P S, Erdos, M R, Graessler, J, Kovacs, P, Morken, M A, Narisu, N, Payne, F, Stancakova, A, Swift, A J, Tonjes, A, Bornstein, S R, Cauchi, S, Froguel, P, Meyre, D, Schwarz, P E H, Haring, H U, Smith, U, Boehnke, M, Bergman, R N, Collins, F S, Mohlke, K L, Tuomilehto, J, Quertemous, T, Lind, L, Hansen, T, Pedersen, O, Walker, M, Pfeiffer, A F H, Spranger, J, Stumvoll, M, Meigs, J B, Wareham, N J, Kuusisto, J, Laakso, M, Langenberg, C, Dupuis, J, Watanabe, R M, Florez, J C, Ingelsson, E, McCarthy, M I, Prokopenko, I & Investigators, M 2014, ' Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity ', Diabetes, vol. 63, no. 6, pp. 2158-2171 . https://doi.org/10.2337/db13-0949Test

مصطلحات موضوعية: Male, Endocrinology, Diabetes and Metabolism, Insulin Resistance/genetics, Type 2 diabetes, Medical and Health Sciences, Endocrinology, 0302 clinical medicine, Gene Frequency, Risk Factors, Insulin-Secreting Cells, Insulin Secretion, 2.1 Biological and endogenous factors, Cluster Analysis, Insulin, Aetiology, 2. Zero hunger, Genetics, 0303 health sciences, SLC30A8, Medicine (all), Diabetes, Single Nucleotide, Diabetes and Metabolism, Diabetes Mellitus, Type 2/genetics, Female, Type 2, Insulin processing, medicine.medical_specialty, Insulin/metabolism, Quantitative Trait Loci, Socio-culturale, 030209 endocrinology & metabolism, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, MAGIC Investigators, Endocrinology & Metabolism, 03 medical and health sciences, Insulin-Secreting Cells/metabolism, Insulin resistance, Clinical Research, Alleles, Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Resistance, Transcription Factors, Genetic Predisposition to Disease, Internal Medicine, Diabetes mellitus, Internal medicine, Genetic model, Diabetes Mellitus, medicine, Transcription Factors/metabolism, Polymorphism, Metabolic and endocrine, 030304 developmental biology, Glycemic, Prevention, medicine.disease, biology.protein, Quantitative Trait Loci/genetics, TCF7L2

الوصف: 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 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used 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 cluster (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 (TCF712, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 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. Patients with established type 2 diabetes display both b-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 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used 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 cluster (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 (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 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.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ec76408386665bb3ac65c80f7efd345Test
https://doi.org/10.2337/db13-0949Test

المؤلفون: Lori L. Bonnycastle, Henna Cederberg, Alena Stančáková, Jussi Paananen, Pasi Soininen, Mika Ala-Korpela, Francis S. Collins, Niyas K. Saleem, Jussi Pihlajamäki, Jagadish Vangipurapu, Antti J. Kangas, Michael Boehnke, Yuvaraj Mahendran, Päivi Pajukanta, Karen L. Mohlke, Mete Civelek, Johanna Kuusisto, Mario A. Morken, Markku Laakso, Aldons J. Lusis

المصدر: Diabetes

مصطلحات موضوعية: Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Adipose tissue, 030209 endocrinology & metabolism, Ketone Bodies, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, White People, Acetoacetates, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Predictive Value of Tests, Risk Factors, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, education, Finland, Original Research, 030304 developmental biology, Metabolic Syndrome, 0303 health sciences, education.field_of_study, Glucose tolerance test, 3-Hydroxybutyric Acid, medicine.diagnostic_test, Genetics/Genomes/Proteomics/Metabolomics, Fasting, Glucose Tolerance Test, Middle Aged, medicine.disease, 3. Good health, Endocrinology, Diabetes Mellitus, Type 2, Area Under Curve, Hyperglycemia, Ketone bodies, Metabolic syndrome, Biomarkers, Genome-Wide Association Study

الوصف: We investigated the association of the levels of ketone bodies (KBs) with hyperglycemia and with 62 genetic risk variants regulating glucose levels or type 2 diabetes in the population-based Metabolic Syndrome in Men (METSIM) study, including 9,398 Finnish men without diabetes or newly diagnosed type 2 diabetes. Increasing fasting and 2-h plasma glucose levels were associated with elevated levels of acetoacetate (AcAc) and β-hydroxybutyrate (BHB). AcAc and BHB predicted an increase in the glucose area under the curve in an oral glucose tolerance test, and AcAc predicted the conversion to type 2 diabetes in a 5-year follow-up of the METSIM cohort. Impaired insulin secretion, but not insulin resistance, explained these findings. Of the 62 single nucleotide polymorphisms associated with the risk of type 2 diabetes or hyperglycemia, the glucose-increasing C allele of GCKR significantly associated with elevated levels of fasting BHB levels. Adipose tissue mRNA expression levels of genes involved in ketolysis were significantly associated with insulin sensitivity (Matsuda index). In conclusion, high levels of KBs predicted subsequent worsening of hyperglycemia, and a common variant of GCKR was significantly associated with BHB levels.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::54e1c59be6633575f8252cac23cf204fTest
https://doi.org/10.2337/db12-1363Test