Sabrina Prudente1, Diego Bailetti2, Christine Mendonca3, Gaia Chiara Mannino4, Andrea Fontana5, Francesco Andreozzi6, Timothy Hastings3, Luana Mercuri7, Federica Alberico7, Giorgio Basile2, Massimiliano Copetti5, Giorgio Sesti6, Alessandro Doria8, Vincenzo Trischitta9. 1. IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy. Electronic address: s.prudente@css-mendel.it. 2. IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy. 3. Research Division, Joslin Diabetes Center, Boston, MA, USA. 4. Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy. 5. IRCCS Casa Sollievo della Sofferenza, Unit of Biostatistics, San Giovanni Rotondo, Italy. 6. Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy. 7. IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy. 8. Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. 9. IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy; IRCSS Casa Sollievo della Sofferenza, Research Unit of Diabetes and Endocrine Diseases, San Giovanni Rotondo, Italy. Electronic address: vincenzo.trischitta@uniroma1.it.
Abstract
OBJECTIVE: Genes that modulate insulin sensitivity may also be involved in shaping the risk of coronary artery disease (CAD). The relatively common TRIB3 Q84R polymorphism (rs2295490) has been associated with abnormal insulin signaling, endothelial dysfunction, insulin resistance, and pro-atherogenic phenotypes. The aim of our study was to investigate the association between low-frequency TRIB3 coding variants and CAD in patients with type 2 diabetes (T2D). METHODS: Three case-control studies for CAD from Italy and US were analyzed, for a total of 1565 individuals, all with type 2 diabetes. Infrequent variants were identified by re-sequencing TRIB3 exons in 140 "extreme cases" and 140 "super-controls" and then genotyped in all study subjects. RESULTS: TRIB3 infrequent variants (n = 8), considered according to a collapsing rare variants framework, were significantly associated with CAD in diabetic patients from Italy (n = 700, OR = 0.43, 95% CI 0.20-0.91; p = 0.027), but not from the US (n = 865, OR = 1.22, 95% CI 0.69-2.18; p = 0.49). In the Italian sets, the association was especially strong among individuals who also carried the common R84 variant. CONCLUSION: Although preliminary, our finding suggests a role of TRIB3 low-frequency variants on CAD among Italian patients with T2D. Further studies are needed to address the role of TRIB3 infrequent variants in other populations of both European and non-European ancestries.
OBJECTIVE: Genes that modulate insulin sensitivity may also be involved in shaping the risk of coronary artery disease (CAD). The relatively common TRIB3Q84R polymorphism (rs2295490) has been associated with abnormal insulin signaling, endothelial dysfunction, insulin resistance, and pro-atherogenic phenotypes. The aim of our study was to investigate the association between low-frequency TRIB3 coding variants and CAD in patients with type 2 diabetes (T2D). METHODS: Three case-control studies for CAD from Italy and US were analyzed, for a total of 1565 individuals, all with type 2 diabetes. Infrequent variants were identified by re-sequencing TRIB3 exons in 140 "extreme cases" and 140 "super-controls" and then genotyped in all study subjects. RESULTS:TRIB3 infrequent variants (n = 8), considered according to a collapsing rare variants framework, were significantly associated with CAD in diabeticpatients from Italy (n = 700, OR = 0.43, 95% CI 0.20-0.91; p = 0.027), but not from the US (n = 865, OR = 1.22, 95% CI 0.69-2.18; p = 0.49). In the Italian sets, the association was especially strong among individuals who also carried the common R84 variant. CONCLUSION: Although preliminary, our finding suggests a role of TRIB3 low-frequency variants on CAD among Italian patients with T2D. Further studies are needed to address the role of TRIB3 infrequent variants in other populations of both European and non-European ancestries.
Authors: Panos Deloukas; Stavroula Kanoni; Christina Willenborg; Martin Farrall; Themistocles L Assimes; John R Thompson; Erik Ingelsson; Danish Saleheen; Jeanette Erdmann; Benjamin A Goldstein; Kathleen Stirrups; Inke R König; Jean-Baptiste Cazier; Asa Johansson; Alistair S Hall; Jong-Young Lee; Cristen J Willer; John C Chambers; Tõnu Esko; Lasse Folkersen; Anuj Goel; Elin Grundberg; Aki S Havulinna; Weang K Ho; Jemma C Hopewell; Niclas Eriksson; Marcus E Kleber; Kati Kristiansson; Per Lundmark; Leo-Pekka Lyytikäinen; Suzanne Rafelt; Dmitry Shungin; Rona J Strawbridge; Gudmar Thorleifsson; Emmi Tikkanen; Natalie Van Zuydam; Benjamin F Voight; Lindsay L Waite; Weihua Zhang; Andreas Ziegler; Devin Absher; David Altshuler; Anthony J Balmforth; Inês Barroso; Peter S Braund; Christof Burgdorf; Simone Claudi-Boehm; David Cox; Maria Dimitriou; Ron Do; Alex S F Doney; NourEddine El Mokhtari; Per Eriksson; Krista Fischer; Pierre Fontanillas; Anders Franco-Cereceda; Bruna Gigante; Leif Groop; Stefan Gustafsson; Jörg Hager; Göran Hallmans; Bok-Ghee Han; Sarah E Hunt; Hyun M Kang; Thomas Illig; Thorsten Kessler; Joshua W Knowles; Genovefa Kolovou; Johanna Kuusisto; Claudia Langenberg; Cordelia Langford; Karin Leander; Marja-Liisa Lokki; Anders Lundmark; Mark I McCarthy; Christa Meisinger; Olle Melander; Evelin Mihailov; Seraya Maouche; Andrew D Morris; Martina Müller-Nurasyid; Kjell Nikus; John F Peden; N William Rayner; Asif Rasheed; Silke Rosinger; Diana Rubin; Moritz P Rumpf; Arne Schäfer; Mohan Sivananthan; Ci Song; Alexandre F R Stewart; Sian-Tsung Tan; Gudmundur Thorgeirsson; C Ellen van der Schoot; Peter J Wagner; George A Wells; Philipp S Wild; Tsun-Po Yang; Philippe Amouyel; Dominique Arveiler; Hanneke Basart; Michael Boehnke; Eric Boerwinkle; Paolo Brambilla; Francois Cambien; Adrienne L Cupples; Ulf de Faire; Abbas Dehghan; Patrick Diemert; Stephen E Epstein; Alun Evans; Marco M Ferrario; Jean Ferrières; Dominique Gauguier; Alan S Go; Alison H Goodall; Villi Gudnason; Stanley L Hazen; Hilma Holm; Carlos Iribarren; Yangsoo Jang; Mika Kähönen; Frank Kee; Hyo-Soo Kim; Norman Klopp; Wolfgang Koenig; Wolfgang Kratzer; Kari Kuulasmaa; Markku Laakso; Reijo Laaksonen; Ji-Young Lee; Lars Lind; Willem H Ouwehand; Sarah Parish; Jeong E Park; Nancy L Pedersen; Annette Peters; Thomas Quertermous; Daniel J Rader; Veikko Salomaa; Eric Schadt; Svati H Shah; Juha Sinisalo; Klaus Stark; Kari Stefansson; David-Alexandre Trégouët; Jarmo Virtamo; Lars Wallentin; Nicholas Wareham; Martina E Zimmermann; Markku S Nieminen; Christian Hengstenberg; Manjinder S Sandhu; Tomi Pastinen; Ann-Christine Syvänen; G Kees Hovingh; George Dedoussis; Paul W Franks; Terho Lehtimäki; Andres Metspalu; Pierre A Zalloua; Agneta Siegbahn; Stefan Schreiber; Samuli Ripatti; Stefan S Blankenberg; Markus Perola; Robert Clarke; Bernhard O Boehm; Christopher O'Donnell; Muredach P Reilly; Winfried März; Rory Collins; Sekar Kathiresan; Anders Hamsten; Jaspal S Kooner; Unnur Thorsteinsdottir; John Danesh; Colin N A Palmer; Robert Roberts; Hugh Watkins; Heribert Schunkert; Nilesh J Samani Journal: Nat Genet Date: 2012-12-02 Impact factor: 38.330
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