Claudia Menzaghi1, Andrea Fontana2, Massimiliano Copetti2, Stefano Rizza3, Belinda Spoto4, Patinut Buranasupkajorn5, Giovanni Tripepi4, Antonella Marucci6, Diego Bailetti7, Timothy Hastings8, Alessandra Testa4, Christine Mendonca8, Francesca Mallamaci4, Salvatore De Cosmo9, Simonetta Bacci9, Massimo Federici3, Alessandro Doria5, Carmine Zoccali4, Vincenzo Trischitta10. 1. Research Unit of Diabetes and Endocrine Diseases IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. Electronic address: c.menzaghi@operapadrepio.it. 2. Unit of Biostatistics IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 3. Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. 4. CNR-IBIM, Research Unit of Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension, Reggio Calabria, Italy. 5. Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. 6. Research Unit of Diabetes and Endocrine Diseases IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 7. IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Italy. 8. Research Division, Joslin Diabetes Center, Boston, MA, USA. 9. Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 10. Research Unit of Diabetes and Endocrine Diseases IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University of Rome, Italy. Electronic address: vincenzo.trischitta@uniroma1.it.
Abstract
OBJECTIVE: We have previously reported the combined effect of SNPs perturbing insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events. We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1851 Whites of European ancestry. METHODS: We investigated a first sample of 721 patients, 232 deaths, 3389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5325 py. RESULTS: In the first sample, individuals carrying 1 or ≥ 2 risk alleles had 33% (p = 0.06) and 51% (p = 0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥ 2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR = 1.34, 95%CI = 1.08-1.67; p = 0.008), and as compared to those carrying only one risk allele (HR = 1.41, 95%CI = 1.13-1.75; p = 0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status. CONCLUSION: Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk.
OBJECTIVE: We have previously reported the combined effect of SNPs perturbing insulin signaling (ENPP1 K121Q, rs1044498; IRS1G972R, rs1801278; TRIB3Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events. We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1851 Whites of European ancestry. METHODS: We investigated a first sample of 721 patients, 232 deaths, 3389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5325 py. RESULTS: In the first sample, individuals carrying 1 or ≥ 2 risk alleles had 33% (p = 0.06) and 51% (p = 0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥ 2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR = 1.34, 95%CI = 1.08-1.67; p = 0.008), and as compared to those carrying only one risk allele (HR = 1.41, 95%CI = 1.13-1.75; p = 0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status. CONCLUSION: Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk.
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Authors: Andrew P Morris; Benjamin F Voight; Tanya M Teslovich; Teresa Ferreira; Ayellet V Segrè; Valgerdur Steinthorsdottir; Rona J Strawbridge; Hassan Khan; Harald Grallert; Anubha Mahajan; Inga Prokopenko; Hyun Min Kang; Christian Dina; Tonu Esko; Ross M Fraser; Stavroula Kanoni; Ashish Kumar; Vasiliki Lagou; Claudia Langenberg; Jian'an Luan; Cecilia M Lindgren; Martina Müller-Nurasyid; Sonali Pechlivanis; N William Rayner; Laura J Scott; Steven Wiltshire; Loic Yengo; Leena Kinnunen; Elizabeth J Rossin; Soumya Raychaudhuri; Andrew D Johnson; Antigone S Dimas; Ruth J F Loos; Sailaja Vedantam; Han Chen; Jose C Florez; Caroline Fox; Ching-Ti Liu; Denis Rybin; David J Couper; Wen Hong L Kao; Man Li; Marilyn C Cornelis; Peter Kraft; Qi Sun; Rob M van Dam; Heather M Stringham; Peter S Chines; Krista Fischer; Pierre Fontanillas; Oddgeir L Holmen; Sarah E Hunt; Anne U Jackson; Augustine Kong; Robert Lawrence; Julia Meyer; John R B Perry; Carl G P Platou; Simon Potter; Emil Rehnberg; Neil Robertson; Suthesh Sivapalaratnam; Alena Stančáková; Kathleen Stirrups; Gudmar Thorleifsson; Emmi Tikkanen; Andrew R Wood; Peter Almgren; Mustafa Atalay; Rafn Benediktsson; Lori L Bonnycastle; Noël Burtt; Jason Carey; Guillaume Charpentier; Andrew T Crenshaw; Alex S F Doney; Mozhgan Dorkhan; Sarah Edkins; Valur Emilsson; Elodie Eury; Tom Forsen; Karl Gertow; Bruna Gigante; George B Grant; Christopher J Groves; Candace Guiducci; Christian Herder; Astradur B Hreidarsson; Jennie Hui; Alan James; Anna Jonsson; Wolfgang Rathmann; Norman Klopp; Jasmina Kravic; Kaarel Krjutškov; Cordelia Langford; Karin Leander; Eero Lindholm; Stéphane Lobbens; Satu Männistö; Ghazala Mirza; Thomas W Mühleisen; Bill Musk; Melissa Parkin; Loukianos Rallidis; Jouko Saramies; Bengt Sennblad; Sonia Shah; Gunnar Sigurðsson; Angela Silveira; Gerald Steinbach; Barbara Thorand; Joseph Trakalo; Fabrizio Veglia; Roman Wennauer; Wendy Winckler; Delilah Zabaneh; Harry Campbell; Cornelia van Duijn; Andre G Uitterlinden; Albert Hofman; Eric Sijbrands; Goncalo R Abecasis; Katharine R Owen; Eleftheria Zeggini; Mieke D Trip; Nita G Forouhi; Ann-Christine Syvänen; Johan G Eriksson; Leena Peltonen; Markus M Nöthen; Beverley Balkau; Colin N A Palmer; Valeriya Lyssenko; Tiinamaija Tuomi; Bo Isomaa; David J Hunter; Lu Qi; Alan R Shuldiner; Michael Roden; Ines Barroso; Tom Wilsgaard; John Beilby; Kees Hovingh; Jackie F Price; James F Wilson; Rainer Rauramaa; Timo A Lakka; Lars Lind; George Dedoussis; Inger Njølstad; Nancy L Pedersen; Kay-Tee Khaw; Nicholas J Wareham; Sirkka M Keinanen-Kiukaanniemi; Timo E Saaristo; Eeva Korpi-Hyövälti; Juha Saltevo; Markku Laakso; Johanna Kuusisto; Andres Metspalu; Francis S Collins; Karen L Mohlke; Richard N Bergman; Jaakko Tuomilehto; Bernhard O Boehm; Christian Gieger; Kristian Hveem; Stephane Cauchi; Philippe Froguel; Damiano Baldassarre; Elena Tremoli; Steve E Humphries; Danish Saleheen; John Danesh; Erik Ingelsson; Samuli Ripatti; Veikko Salomaa; Raimund Erbel; Karl-Heinz Jöckel; Susanne Moebus; Annette Peters; Thomas Illig; Ulf de Faire; Anders Hamsten; Andrew D Morris; Peter J Donnelly; Timothy M Frayling; Andrew T Hattersley; Eric Boerwinkle; Olle Melander; Sekar Kathiresan; Peter M Nilsson; Panos Deloukas; Unnur Thorsteinsdottir; Leif C Groop; Kari Stefansson; Frank Hu; James S Pankow; Josée Dupuis; James B Meigs; David Altshuler; Michael Boehnke; Mark I McCarthy Journal: Nat Genet Date: 2012-08-12 Impact factor: 38.330