Joint effect of insulin signaling genes on all-cause mortality

• Published in: Atherosclerosis 2014-12, Vol.237 (2), p.639-644
• Main Authors: Menzaghi, Claudia, Fontana, Andrea, Copetti, Massimiliano, Rizza, Stefano, Spoto, Belinda, Buranasupkajorn, Patinut, Tripepi, Giovanni, Marucci, Antonella, Bailetti, Diego, Hastings, Timothy, Testa, Alessandra, Mendonca, Christine, Mallamaci, Francesca, De Cosmo, Salvatore, Bacci, Simonetta, Federici, Massimo, Doria, Alessandro, Zoccali, Carmine, Trischitta, Vincenzo
• Format: Article
• Language: English
• Subjects: Aged; Alleles; Atherosclerosis - blood; Atherosclerosis - diagnosis; Atherosclerosis - mortality; Cardiovascular; Cardiovascular Diseases - blood; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - mortality; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - mortality; ENPP1; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Insulin - metabolism; Insulin Resistance; IRS1; Italy - epidemiology; Male; Middle Aged; Mortality; Myocardial Infarction - blood; Myocardial Infarction - diagnosis; Myocardial Infarction - mortality; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; Prospective study; Signal Transduction; Treatment Outcome; TRIB3
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2014.10.005

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.