title: Joint effect of insulin signaling genes on all-cause mortality.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Research Unit of Diabetes and Endocrine Diseases IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. Electronic address: c.menzaghi@operapadrepio.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Menzaghi
authors.affiliation: Unit of Biostatistics IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Unit of Biostatistics IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizza
authors.affiliation: CNR-IBIM, Research Unit of Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension, Reggio Calabria, Italy.
authors.forename: Belinda
authors.initials: B
authors.lastname: Spoto
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Patinut
authors.initials: P
authors.lastname: Buranasupkajorn
authors.affiliation: CNR-IBIM, Research Unit of Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension, Reggio Calabria, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tripepi
authors.affiliation: Research Unit of Diabetes and Endocrine Diseases IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Marucci
authors.affiliation: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Bailetti
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hastings
authors.affiliation: CNR-IBIM, Research Unit of Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension, Reggio Calabria, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Testa
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Mendonca
authors.affiliation: CNR-IBIM, Research Unit of Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension, Reggio Calabria, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mallamaci
authors.affiliation: Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Cosmo
authors.affiliation: Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bacci
authors.affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.affiliation: CNR-IBIM, Research Unit of Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension, Reggio Calabria, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
authors.affiliation: 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.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D000368:Aged; D000483:Alleles; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009203:Myocardial Infarction / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D007328:Insulin
keywords: ENPP1; IRS1; Prospective study; TRIB3