BACKGROUND AND AIMS: Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. METHODS AND RESULTS: Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P = 5 × 10⁻⁸) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. CONCLUSIONS: We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.
BACKGROUND AND AIMS: Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. METHODS AND RESULTS: Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P = 5 × 10⁻⁸) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. CONCLUSIONS: We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.
Authors: C M Lindgren; M M Mahtani; E Widén; M I McCarthy; M J Daly; A Kirby; M P Reeve; L Kruglyak; A Parker; J Meyer; P Almgren; M Lehto; T Kanninen; T Tuomi; L C Groop; E S Lander Journal: Am J Hum Genet Date: 2002-01-09 Impact factor: 11.025
Authors: M G Ehm; M C Karnoub; H Sakul; K Gottschalk; D C Holt; J L Weber; D Vaske; D Briley; L Briley; J Kopf; P McMillen; Q Nguyen; M Reisman; E H Lai; G Joslyn; N S Shepherd; C Bell; M J Wagner; D K Burns Journal: Am J Hum Genet Date: 2000-05-02 Impact factor: 11.025
Authors: A E Civitarese; C P Jenkinson; D Richardson; M Bajaj; K Cusi; S Kashyap; R Berria; R Belfort; R A DeFronzo; L J Mandarino; E Ravussin Journal: Diabetologia Date: 2004-04-23 Impact factor: 10.122
Authors: C Debard; M Laville; V Berbe; E Loizon; C Guillet; B Morio-Liondore; Y Boirie; H Vidal Journal: Diabetologia Date: 2004-05-01 Impact factor: 10.122
Authors: 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; 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; 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; 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 Journal: PLoS Genet Date: 2012-03-29 Impact factor: 5.917
Authors: Ping An; Robert J Straka; Toni I Pollin; Mary F Feitosa; Mary K Wojczynski; E Warwick Daw; Jeffrey R O'Connell; Quince Gibson; Kathleen A Ryan; Paul N Hopkins; Michael Y Tsai; Chao-Qiang Lai; Michael A Province; Jose M Ordovas; Alan R Shuldiner; Donna K Arnett; Ingrid B Borecki Journal: Hum Genet Date: 2014-03-07 Impact factor: 4.132
Authors: S Aslibekyan; A N Do; H Xu; S Li; M R Irvin; D Zhi; H K Tiwari; D M Absher; A R Shuldiner; T Zhang; W Chen; K Tanner; C Hong; B D Mitchell; G Berenson; D K Arnett Journal: Nutr Metab Cardiovasc Dis Date: 2016-11-23 Impact factor: 4.222
Authors: Patricia Casas-Agustench; Donna K Arnett; Caren E Smith; Chao-Qiang Lai; Laurence D Parnell; Ingrid B Borecki; Alexis C Frazier-Wood; Matthew Allison; Yii-Der Ida Chen; Kent D Taylor; Stephen S Rich; Jerome I Rotter; Yu-Chi Lee; José M Ordovás Journal: J Acad Nutr Diet Date: 2014-05-01 Impact factor: 4.910
Authors: Pratyaydipta Rudra; K Alaine Broadaway; Erin B Ware; Min A Jhun; Lawrence F Bielak; Wei Zhao; Jennifer A Smith; Patricia A Peyser; Sharon L R Kardia; Michael P Epstein; Debashis Ghosh Journal: Genet Epidemiol Date: 2018-03-30 Impact factor: 2.135
Authors: Marguerite R Irvin; Degui Zhi; Stella Aslibekyan; Steven A Claas; Devin M Absher; Jose M Ordovas; Hemant K Tiwari; Steve Watkins; Donna K Arnett Journal: PLoS One Date: 2014-06-06 Impact factor: 3.240