Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Authors:
Dr. Najaf Amin, PhD
Dr. Najaf Amin, PhD
Erasmus University Medical Center
Rotterdam | Netherlands
Dr. Kyunga Kim, PhD
Dr. Kyunga Kim, PhD
Samsung Medical Center
Professor
Seoul | Korea, Republic of
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 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 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 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 Frank B Hu 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 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 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 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

PLoS Genet 2012 29;8(3):e1002607. Epub 2012 Mar 29.

Department of Epidemiology, Biostatistics, and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University, Montreal, Canada.

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<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

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http://dx.doi.org/10.1371/journal.pgen.1002607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315470PMC
September 2012
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References

(Supplied by CrossRef)
Plasma Adiponectin Levels and Risk of Myocardial Infarction in Men.
T Pischon et al.
JAMA: The Journal of the American Medical Association 2004

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