Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Rona J. Strawbridge, Josée Dupuis, Inga Prokopenko, Adam Barker, Emma Ahlqvist, Denis Rybin, John R. Petrie, Mary E. Travers, Nabila Bouatia-Naji, Antigone S. Dimas, Alexandra C. Nica, Eleanor Wheeler, Han Chen, Benjamin F. Voight, Jalal Taneera, Stavroula Kanoni, John F. Peden, Fabiola Turrini, Stefan Gustafsson, Carina ZabenaPeter Almgren, David J.P. Barker, Daniel Barnes, Elaine M. Dennison, Johan G. Eriksson, Per Eriksson, Elodie Eury, Lasse Folkersen, Caroline S. Fox, Timothy M. Frayling, Anuj Goel, Harvest F. Gu, Momoko Horikoshi, Bo Isomaa, Anne U. Jackson, Karen A. Jameson, Eero Kajantie, Julie Kerr-Conte, Teemu Kuulasmaa, Johanna Kuusisto, Ruth J.F. Loos, Jian'an Luan, Konstantinos Makrilakis, Alisa K. Manning, María Teresa Martínez-Larrad, Narisu Narisu, Maria Nastase Mannila, John Öhrvik, Clive Osmond, Laura Pascoe, Felicity Payne, Avan A. Sayer, Bengt Sennblad, Angela Silveira, Alena Stančcáková, Kathy Stirrups, Amy J. Swift, Ann Christine Syvänen, Tiinamaija Tuomi, Ferdinand M. Van't Hooft, Mark Walker, Michael N. Weedon, Weijia Xie, Björn Zethelius, 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, Steven A. McCarroll, Oliver M. Hofmann, Lu Qi, Ayellet V. Segre, Mandy Van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Bostrom, Bert Bravenboer, Suzannah Bumpstead, Noisel 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, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Paul R.V. Johnson, Torben Jorgensen, Wen H.L. Kao, Norman Klopp, Augustine Kong, Peter Kraft, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Peter Nilsson, Katharine R. Owen, John R.B. Perry, Ann Kristin Petersen, Carl Platou, Christine Proenca, 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 Sparso, Klaus Strassburger, Heather M. Stringham, Qi Sun, Barbara Thorand, Jean Tichet, Rob M. Van Dam, Timon W. Van Haeften, Thijs Van Herpt, Jana V. Van Vliet-Ostaptchouk, G. Bragi Walters, Cisca Wijmenga, Jacqueline C.M. 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 G. Uitterlinden, 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, 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, Elizabeth K. Speliotes, Sonja I. Berndt, Keri L. Monda, Hana Lango Allen, Reedik Magi, Joshua C. Randall, Sailaja Vedantam, Thomas W. Winkler, Tsegaselassie Workalemahu, Iris M. Heid, Andrew R. Wood, Robert J. Weyant, Karol Estrada, Liming Liang, James Nemesh, Ju Hyun Park, Tuomas O. Kilpelainen, Jian Yang, Tonu Esko, Mary F. Feitosa, Zoltan Kutalik, Massimo Mangino, Andre Scherag, Albert Vernon Smith, Jing Hua Zhao, Katja K. Aben, Devin M. Absher, Anna L. Dixon, Eva Fisher, Nicole L. Glazer, Michael E. Goddard, Nancy L. Heard-Costa, Volker Hoesel, Jouke Jan Hottenga, Asa Johansson, Toby Johnson, Shamika Ketkar, Claudia Lamina, Shengxu Li, Miriam F. Moffatt, Richard H. Myers, Marjolein J. Peters, Michael Preuss, Samuli Ripatti, Fernando Rivadeneira, Camilla Sandholt, Nicholas J. Timpson, Jonathan P. Tyrer, Sophie Van Wingerden, Charles C. White, Fredrik Wiklund, Christina Barlassina, Daniel I. Chasman, Matthew N. Cooper, John Olov Jansson, Robert W. Lawrence, Niina Pellikka, Jianxin Shi, Elisabeth Thiering, Helene Alavere, Maria T.S. Alibrandi, Alice M. Arnold, Thor Aspelund, Larry D. Atwood, Anthony J. Balmforth, Yoav Ben-Shlomo, Sven Bergmann, Heike Biebermann, Alexandra I.F. Blakemore, Tanja Boes, Stefan R. Bornstein, Morris J. Brown, Thomas A. Buchanan, Fabio Busonero, Francesco P. Cappuccio, Christine Cavalcanti-Proenca, Yii Der Ida Chen, Chih Mei Chen, Robert Clarke, Lachlan Coin, John Connell, Ian N.M. Day, Martin Den Heijer, Jubao Duan, Shah Ebrahim, Paul Elliott, Roberto Elosua, Gudny Eiriksdottir, Maurizio F. Facheris, Stephan B. Felix, Pamela Fischer-Posovszky, Aaron R. Folsom, Nele Friedrich, Nelson B. Freimer, Mao Fu, Stefan Gaget, Pablo V. Gejman, Eco J.C. Geus, Anette P. Gjesing, Philippe Goyette, Jurgen Grasler, Danielle M. Greenawalt, Vilmundur Gudnason, Anna Liisa Hartikainen, Alistair S. Hall, Aki S. Havulinna, Caroline Hayward, Andrew C. Heath, Christian Hengstenberg, Andrew A. Hicks, Anke Hinney, Georg Homuth, Jennie Hui, Wilmar Igl, Carlos Iribarren, Kevin B. Jacobs, Ivonne Jarick, Elizabeth Jewell, Ulrich John, Pekka Jousilahti, Antti Jula, Marika Kaakinen, Lee M. Kaplan, Sekar Kathiresan, Johannes Kettunen, Leena Kinnunen, Joshua W. Knowles, Ivana Kolcic, Inke R. König, Seppo Koskinen, Peter Kovacs, Kirsti Kvaloy, Jaana Laitinen, Olivier Lantieri, Chiara Lanzani, Lenore J. Launer, Cecile Lecoeur, Terho Lehtimaki, Guillaume Lettre, Jianjun Liu, Marja Liisa Lokki, Mattias Lorentzon, Robert N. Luben, Barbara Ludwig, Paolo Manunta, Diana Marek, Nicholas G. Martin, Wendy L. McArdle, Anne McCarthy, Barbara McKnight, Olle Melander, David Meyre, Grant W. Montgomery, Rosanda Mulic, Julius S. Ngwa, Mari Nelis, Matt J. Neville, Dale R. Nyholt, Christopher J. O'Donnell, S. O'Rahilly, Ken K. Ong, Ben Oostra, Guillaume Pare, Alex N. Parker, Markus Perola, Irene Pichler, Kirsi H. Pietilainen, Carl G.P. Platou, Ozren Polasek, Anneli Pouta, Suzanne Rafelt, Olli Raitakari, Nigel W. Rayner, Martin Ridderstrale, Winfried Rief, Aimo Ruokonen, Peter Rzehak, Veikko Salomaa, Alan R. Sanders, Manjinder S. Sandhu, Serena Sanna, Jouko Saramies, Markku J. Savolainen, Susann Scherag, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, Kaisa Silander, Juha Sinisalo, David S. Siscovick, Jan H. Smit, Nicole Soranzo, Ulla Sovio, Jonathan Stephens, Ida Surakka, Mari Liis Tammesoo, Jean Claude Tardif, Maris Teder-Laving, Tanya M. Teslovich, John R. Thompson, Brian Thomson, Anke Tonjes, Joyce B.J. Van Meurs, Gert Jan Van Ommen, Vincent Vatin, Jorma Viikari, Sophie Visvikis-Siest, Veronique Vitart, Carla I.G. Vogel, Lindsay L. Waite, Henri Wallaschofski, Elisabeth Widen, Susanna Wiegand, Sarah H. Wild, Gonneke Willemsen, Daniel R. Witte, Jianfeng Xu, Qunyuan Zhang, Lina Zgaga, Andreas Ziegler, Paavo Zitting, John P. Beilby, I. Sadaf Farooqi, Johannes Hebebrand, Heikki V. Huikuri, Alan L. James, Mika Kahonen, Douglas F. Levinson, Fabio Macciardi, Markku S. Nieminen, Claes Ohlsson, Lyle J. Palmer, Paul M. Ridker, Michael Stumvoll, Jacques S. Beckmann, Heiner Boeing, Dorret I. Boomsma, Mark J. Caulfield, Stephen J. Chanock, L. Adrienne Cupples, George Davey Smith, Jeanette Erdmann, Henrik Gronberg, Per Hall, Tamara B. Harris, Richard B. Hayes, Joachim Heinrich, Marjo Riitta Jarvelin, Jaakko Kaprio, Fredrik Karpe, Kay Tee Khaw, Lambertus A. Kiemeney, Heiko Krude, Debbie A. Lawlor, Andres Metspalu, Patricia B. Munroe, Willem H. Ouwehand, Brenda W. Penninx, Annette Peters, Thomas Quertermous, Thomas Reinehr, Aila Rissanen, Nilesh J. Samani, Peter E.H. Schwarz, Alan R. Shuldiner, Timothy D. Spector, Manuela Uda, Timo T. Valle, Martin Wabitsch, Gerard Waeber, Hugh Watkins, Alan F. Wright, M. Carola Zillikens, Nilanjan Chatterjee, Shaun Purcell, Eric E. Schadt, Peter M. Visscher, Themistocles L. Assimes, Ingrid B. Borecki, Panos Deloukas, Talin Haritunians, Robert C. Kaplan, Jeffrey R. O'Connell, Leena Peltonen, David Schlessinger, David P. Strachan, Kari E. North, Joel N. Hirschhorn, Erik Ingelsson, Leopold Parts, Daniel Glass, James Nisbet, Amy Barrett, Magdalena Sekowska, Simon Potter, Elin Grundberg, Kerrin Small, Asa K. Hedman, Veronique Bataille, Jordana Tzenova Bell, Gabriela Surdulescu, Catherine Ingle, Frank O. Nestle, Paola Di Meglio, Josine L. Min, Alicja Wilk, Christopher J. Hammond, Tsun Po Yang, Stephen B. Montgomery, Krina T. Zondervan, Richard Durbin, Kourosh Ahmadi, Emmanouil T. Dermitzakis, Muredach P. Reilly, Hilma Holm, Alexandre F.R. Stewart, Maja Barbalic, Zouhair Aherrahrou, Hooman Allayee, Sonia S. Anand, Karl Andersen, Jeffrey L. Anderson, Diego Ardissino, Stephen G. Ball, Timothy A. Barnes, Diane M. Becker, Lewis C. Becker, Klaus Berger, Joshua C. Bis, S. Matthijs Boekholdt, Peter S. Braund, Mary Susan Burnett, Ian Buysschaert, John F. Carlquist, Li Chen, Veryan Codd, Robert W. Davies, Sven Cichon, George V. Dedoussis, Serkalem Demissie, Abbas Dehghan, Joseph M. Devaney, Patrick Diemert, Ron Do, Angela Doering, Sandra Eifert, Nour Eddine El Mokhtari, Stephen G. Ellis, James C. Engert, Stephen E. Epstein, Ulf De Faire, Marcus Fischer, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Jeffrey R. Gulcher, Eran Halperin, Naomi Hammond, Stanley L. Hazen, Benjamin D. Horne, Gregory T. Jones, J. Wouter Jukema, Michael A. Kaiser, John J.P. Kastelein, Genovefa Kolovou, Reijo Laaksonen, Diether Lambrechts, Karin Leander, Mingyao Li, Wolfgang Lieb, Christina Loley, Andrew J. Lotery, Pier M. Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P. McKeown, Christa Meisinger, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W. Mühleisen, Joseph B. Muhlestein, Thomas Münzel, Kiran Musunuru, Janja Nahrstaedt, Christopher P. Nelson, Markus M. Nöthen, Oliviero Olivieri, Riyaz S. Patel, Chris C. Patterson, Flora Peyvandi, Liming Qu, Arshed A. Quyyumi, Daniel J. Rader, Loukianos S. Rallidis, Catherine Rice, Frits R. Rosendaal, Diana Rubin, M. Lourdes Sampietro, Manj S. Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Jürgen Schrezenmeir, Stephen M. Schwartz, Mohan Sivananthan, Suthesh Sivapalaratnam, Tamara B. Smith, Jaapjan D. Snoep, John A. Spertus, Klaus Stark, Monika Stoll, W. H. Wilson Tang, Stephanie Tennstedt, Gudmundur Thorgeirsson, Maciej Tomaszewski, Andre M. Van Rij, Nick J. Wareham, George A. Wells, Philipp S. Wild, Christina Willenborg, Benjamin J. Wright, Shu Ye, Tanja Zeller, Francois Cambien, Alison H. Goodall, Winfried Marz, Stefan Blankenberg, Robert Roberts, Ruth McPherson, Jemma C. Hopewell, Sarah Parish, Alison Offer, Louise Bowman, Peter Sleight, Jane Armitage, Richard Peto, Rory Collins, John C. Chambers, Nabeel Ahmed, Peter Donnelly, Angad S. Kooner, James Scott, Joban Sehmi, Weihua Zhang, Jaspal Kooner, Maria Sabater-Lleal, Anders Mälarstig, Mai Lis Hellénius, Gunnar Olsson, Stephan Rust, Gerd Assmann, Udo Seedorf, Simona Barlera, Gianni Tognoni, Maria Grazia Franzosi, Pamela Linksted, Halit Ongen, Theodosios Kyriakou, Fiona Green, Martin Farrall, Danish Saleheen, Asif Rasheed, Moazzam Zaidi, Nabi Shah, Maria Samuel, Nadeem Mallick, Muhammad Azhar, Khan Zaman, Adbus Samad, Muhammad Ishaq, Ali Gardezi, Fazal Ur Rehman Memon, Philippe Frossard, John Danesh, Claes Göran Östenson, Lars Lind, Cyrus C. Cooper, Manuel Serrano-Ríos, Ele Ferrannini, Tom J. Forsen, François Pattou, Claudia Langenberg, Anders Hamsten, Jose C. Florez

Research output: Contribution to journalArticle

220 Scopus citations

Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10 -8 ). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10 -4 ), improved b-cell function (P = 1.1 × 10 -5 ), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10 -6 ). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)2624-2634
Number of pages11
JournalDiabetes
Volume60
Issue number10
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Strawbridge, R. J., Dupuis, J., Prokopenko, I., Barker, A., Ahlqvist, E., Rybin, D., Petrie, J. R., Travers, M. E., Bouatia-Naji, N., Dimas, A. S., Nica, A. C., Wheeler, E., Chen, H., Voight, B. F., Taneera, J., Kanoni, S., Peden, J. F., Turrini, F., Gustafsson, S., ... Florez, J. C. (2011). Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes, 60(10), 2624-2634. https://doi.org/10.2337/db11-0415