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. 2014 Dec;237(2):639-44.
doi: 10.1016/j.atherosclerosis.2014.10.005. Epub 2014 Oct 24.

Joint effect of insulin signaling genes on all-cause mortality

Claudia Menzaghi  1 , Andrea Fontana  2 , Massimiliano Copetti  2 , Stefano Rizza  3 , Belinda Spoto  4 , Patinut Buranasupkajorn  5 , Giovanni Tripepi  4 , Antonella Marucci  6 , Diego Bailetti  7 , Timothy Hastings  8 , Alessandra Testa  4 , Christine Mendonca  8 , Francesca Mallamaci  4 , Salvatore De Cosmo  9 , Simonetta Bacci  9 , Massimo Federici  3 , Alessandro Doria  5 , Carmine Zoccali  4 , Vincenzo Trischitta  10
Affiliations

Joint effect of insulin signaling genes on all-cause mortality

Claudia Menzaghi et al. Atherosclerosis. 2014 Dec.

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.

Keywords: ENPP1; IRS1; Prospective study; TRIB3.

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Conflict of interest statement

Competing interests

No potential conflicts of interest relevant to this article were reported.

Figures

Figure 1
Figure 1
Forest plots of random effects meta-analysis of HRs estimates according to individuals with ≥ 2 risk alleles vs individuals with 0 risk allele. Figure 1A: meta-analysis was carried out on GHS, TVAS, CREED, GMS and JKS; Figure 1B: meta-analysis was carried out on GHS, CREED, GMS and JKS.
Figure 2
Figure 2
Hazard ratios (95% CI) of all-cause mortality in all samples according to genotype risk alleles. Hazard ratios were estimated by Cox regression after adjusting for all five study cohorts.
See this image and copyright information in PMC

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