Joint effect of insulin signaling genes on all-cause mortality |
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Authors: | Claudia Menzaghi Andrea Fontana Massimiliano Copetti Stefano Rizza Belinda Spoto Patinut Buranasupkajorn Giovanni Tripepi Antonella Marucci Diego Bailetti Timothy Hastings Alessandra Testa Christine Mendonca Francesca Mallamaci Salvatore De Cosmo Simonetta Bacci Massimo Federici Alessandro Doria Carmine Zoccali Vincenzo Trischitta |
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Institution: | 1. Research Unit of Diabetes and Endocrine Diseases IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy;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;6. Department of Medicine, Harvard Medical School, Boston, MA, USA;g IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, Rome, Italy;h Department of Experimental Medicine, Sapienza University of Rome, Italy;i Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy |
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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. |
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Keywords: | ENPP1 IRS1 TRIB3 Prospective study |
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