AIMS/HYPOTHESIS: The aim of the study was to determine the association between IRS1 G972R polymorphism and type 2 diabetes; published data concerning this association have been conflicting. To obtain further insight into this topic, we performed a meta-analysis of all available case-control studies. METHODS: We performed a meta-analysis of 32 studies (12,076 cases and 11,285 controls). RESULTS: The relatively infrequent R972 variant was not significantly associated with type 2 diabetes (OR 1.09, 95% CI 0.96-1.23, p = 0.184 under a dominant model). Some evidence of heterogeneity was observed across studies (p = 0.1). In the 14 studies (9,713 individuals) in which the mean age at type 2 diabetes diagnosis was available, this variable explained 52% of the heterogeneity (p = 0.03). When these studies were subdivided into tertiles of mean age at diagnosis, the OR for diabetes was 1.48 (95% CI 1.17-1.87), 1.22 (95% CI 0.97-1.53) and 0.88 (95% CI 0.68-1.13) in the youngest, intermediate and oldest tertile, respectively (p = 0.0022 for trend of ORs). CONCLUSIONS/ INTERPRETATION: Our findings illustrate the difficulties of ascertaining the contribution of 'low-frequency-low-risk' variants to type 2 diabetes susceptibility. In the specific context of the R972 variant, approximately 200,000 study individuals would be needed to have 80% power to identify a 9% increase in diabetes risk at a genome-wide significance level. Under these circumstances, a strategy aimed at improving outcome definition and decreasing its heterogeneity may critically enhance our ability to detect genetic effects, thereby decreasing the required sample size. Our data suggest that focusing on early-onset diabetes, which is characterised by a stronger genetic background, may be part of such a strategy.
AIMS/HYPOTHESIS: The aim of the study was to determine the association between IRS1 G972R polymorphism and type 2 diabetes; published data concerning this association have been conflicting. To obtain further insight into this topic, we performed a meta-analysis of all available case-control studies. METHODS: We performed a meta-analysis of 32 studies (12,076 cases and 11,285 controls). RESULTS: The relatively infrequent R972 variant was not significantly associated with type 2 diabetes (OR 1.09, 95% CI 0.96-1.23, p = 0.184 under a dominant model). Some evidence of heterogeneity was observed across studies (p = 0.1). In the 14 studies (9,713 individuals) in which the mean age at type 2 diabetes diagnosis was available, this variable explained 52% of the heterogeneity (p = 0.03). When these studies were subdivided into tertiles of mean age at diagnosis, the OR for diabetes was 1.48 (95% CI 1.17-1.87), 1.22 (95% CI 0.97-1.53) and 0.88 (95% CI 0.68-1.13) in the youngest, intermediate and oldest tertile, respectively (p = 0.0022 for trend of ORs). CONCLUSIONS/ INTERPRETATION: Our findings illustrate the difficulties of ascertaining the contribution of 'low-frequency-low-risk' variants to type 2 diabetes susceptibility. In the specific context of the R972 variant, approximately 200,000 study individuals would be needed to have 80% power to identify a 9% increase in diabetes risk at a genome-wide significance level. Under these circumstances, a strategy aimed at improving outcome definition and decreasing its heterogeneity may critically enhance our ability to detect genetic effects, thereby decreasing the required sample size. Our data suggest that focusing on early-onset diabetes, which is characterised by a stronger genetic background, may be part of such a strategy.
Authors: M Stumvoll; A Fritsche; A Volk; N Stefan; A Madaus; E Maerker; A Teigeler; M Koch; F Machicao; H Häring Journal: Diabetes Date: 2001-04 Impact factor: 9.461
Authors: Eleftheria Zeggini; Laura J Scott; Richa Saxena; Benjamin F Voight; Jonathan L Marchini; Tianle Hu; Paul I W de Bakker; Gonçalo R Abecasis; Peter Almgren; Gitte Andersen; Kristin Ardlie; Kristina Bengtsson Boström; Richard N Bergman; Lori L Bonnycastle; Knut Borch-Johnsen; Noël P Burtt; Hong Chen; Peter S Chines; Mark J Daly; Parimal Deodhar; Chia-Jen Ding; Alex S F Doney; William L Duren; Katherine S Elliott; Michael R Erdos; Timothy M Frayling; Rachel M Freathy; Lauren Gianniny; Harald Grallert; Niels Grarup; Christopher J Groves; Candace Guiducci; Torben Hansen; Christian Herder; Graham A Hitman; Thomas E Hughes; Bo Isomaa; Anne U Jackson; Torben Jørgensen; Augustine Kong; Kari Kubalanza; Finny G Kuruvilla; Johanna Kuusisto; Claudia Langenberg; Hana Lango; Torsten Lauritzen; Yun Li; Cecilia M Lindgren; Valeriya Lyssenko; Amanda F Marvelle; Christa Meisinger; Kristian Midthjell; Karen L Mohlke; Mario A Morken; Andrew D Morris; Narisu Narisu; Peter Nilsson; Katharine R Owen; Colin N A Palmer; Felicity Payne; John R B Perry; Elin Pettersen; Carl Platou; Inga Prokopenko; Lu Qi; Li Qin; Nigel W Rayner; Matthew Rees; Jeffrey J Roix; Anelli Sandbaek; Beverley Shields; Marketa Sjögren; Valgerdur Steinthorsdottir; Heather M Stringham; Amy J Swift; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Nicholas J Timpson; Tiinamaija Tuomi; Jaakko Tuomilehto; Mark Walker; Richard M Watanabe; Michael N Weedon; Cristen J Willer; Thomas Illig; Kristian Hveem; Frank B Hu; Markku Laakso; Kari Stefansson; Oluf Pedersen; Nicholas J Wareham; Inês Barroso; Andrew T Hattersley; Francis S Collins; Leif Groop; Mark I McCarthy; Michael Boehnke; David Altshuler Journal: Nat Genet Date: 2008-03-30 Impact factor: 38.330
Authors: Sekar Kathiresan; Benjamin F Voight; Shaun Purcell; Kiran Musunuru; Diego Ardissino; Pier M Mannucci; Sonia Anand; James C Engert; Nilesh J Samani; Heribert Schunkert; Jeanette Erdmann; Muredach P Reilly; Daniel J Rader; Thomas Morgan; John A Spertus; Monika Stoll; Domenico Girelli; Pascal P McKeown; Chris C Patterson; David S Siscovick; Christopher J O'Donnell; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; Olle Melander; David Altshuler; Diego Ardissino; Pier Angelica Merlini; Carlo Berzuini; Luisa Bernardinelli; Flora Peyvandi; Marco Tubaro; Patrizia Celli; Maurizio Ferrario; Raffaela Fetiveau; Nicola Marziliano; Giorgio Casari; Michele Galli; Flavio Ribichini; Marco Rossi; Francesco Bernardi; Pietro Zonzin; Alberto Piazza; Pier M Mannucci; Stephen M Schwartz; David S Siscovick; Jean Yee; Yechiel Friedlander; Roberto Elosua; Jaume Marrugat; Gavin Lucas; Isaac Subirana; Joan Sala; Rafael Ramos; Sekar Kathiresan; James B Meigs; Gordon Williams; David M Nathan; Calum A MacRae; Christopher J O'Donnell; Veikko Salomaa; Aki S Havulinna; Leena Peltonen; Olle Melander; Goran Berglund; Benjamin F Voight; Sekar Kathiresan; Joel N Hirschhorn; Rosanna Asselta; Stefano Duga; Marta Spreafico; Kiran Musunuru; Mark J Daly; Shaun Purcell; Benjamin F Voight; Shaun Purcell; James Nemesh; Joshua M Korn; Steven A McCarroll; Stephen M Schwartz; Jean Yee; Sekar Kathiresan; Gavin Lucas; Isaac Subirana; Roberto Elosua; Aarti Surti; Candace Guiducci; Lauren Gianniny; Daniel Mirel; Melissa Parkin; Noel Burtt; Stacey B Gabriel; Nilesh J Samani; John R Thompson; Peter S Braund; Benjamin J Wright; Anthony J Balmforth; Stephen G Ball; Alistair S Hall; Heribert Schunkert; Jeanette Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Heribert Schunkert; Nilesh J Samani; Jeanette Erdmann; Willem Ouwehand; Christian Hengstenberg; Panos Deloukas; Michael Scholz; Francois Cambien; Muredach P Reilly; Mingyao Li; Zhen Chen; Robert Wilensky; William Matthai; Atif Qasim; Hakon H Hakonarson; Joe Devaney; Mary-Susan Burnett; Augusto D Pichard; Kenneth M Kent; Lowell Satler; Joseph M Lindsay; Ron Waksman; Christopher W Knouff; Dawn M Waterworth; Max C Walker; Vincent Mooser; Stephen E Epstein; Daniel J Rader; Thomas Scheffold; Klaus Berger; Monika Stoll; Andreas Huge; Domenico Girelli; Nicola Martinelli; Oliviero Olivieri; Roberto Corrocher; Thomas Morgan; John A Spertus; Pascal McKeown; Chris C Patterson; Heribert Schunkert; Erdmann Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke R König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Hilma Hólm; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Kari Stefansson; James C Engert; Ron Do; Changchun Xie; Sonia Anand; Sekar Kathiresan; Diego Ardissino; Pier M Mannucci; David Siscovick; Christopher J O'Donnell; Nilesh J Samani; Olle Melander; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; David Altshuler Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: S Prudente; R Di Paola; S Pezzilli; M Garofolo; O Lamacchia; T Filardi; G C Mannino; L Mercuri; F Alberico; M G Scarale; G Sesti; S Morano; G Penno; M Cignarelli; M Copetti; V Trischitta Journal: Pharmacogenomics J Date: 2017-07-11 Impact factor: 3.550
Authors: N Yiannakouris; J A Cooper; S Shah; F Drenos; H A Ireland; J W Stephens; K-W Li; R Elkeles; I F Godsland; M Kivimaki; A D Hingorani; M Kumari; P J Talmud; S E Humphries Journal: Nutr Metab Cardiovasc Dis Date: 2011-09-14 Impact factor: 4.222