SIRT1 rs7896005 polymorphism affects major vascular outcomes, not all-cause mortality, in Caucasians with type 2 diabetes: A 13-year observational study

Abstract

Aims: SIRT1 exerts effects on ageing and lifespan, as well cardiovascular (CV) disease risk. SIRT1 gene is very polymorph with a few tagging single nucleotide polymorphisms (SNPs) so far identified. Some SNPs, including rs7896005, were associated with type 2 diabetes (T2DM). We aimed to ascertain whether this SNP may be associated with CV disease at baseline as well with these same outcomes and all-cause mortality over a 13-year follow-up.

Materials and methods: Genotypes of SIRT1 gene were determined using TaqMan SNP assay.

Results: Out of 905 T2DM, 9.1% had the AA genotype, 43.2% the AG, and 47.7% the GG. Hardy-Weinberg Equilibrium was met (minor allele frequency 0.306; p = 0.8899). At baseline, there was no difference across genotypes for sex, age, diabetes duration, CV risk factors, treatments, and microangiopathy. Major CV outcomes, myocardial infarction (MI), any coronary heart disease (CHD), and peripheral artery disease (PAD) were more frequent in GG than in AA/AG (p from 0.013 to 0.027), with no association with cerebrovascular events. By fully adjusted regression, GG remained independently related to major CV outcomes, MI, CHD, and PAD. Over follow-up, we recorded 258 major CV events (28.5%; AA/AG 25.2%, GG 32.2%; p = 0.014) with an adjusted hazard ratio (HR) of GG versus AA/AG of 1.296 (95% CI 1.007-1.668, p = 0.044); 169 coronary events (18.7%; AA/AG 15.4%, GG 22.2%; p = 0.006) with HR 1.522 (1.113-2.080, p = 0.008); 79 (8.7%) hospitalisation for heart failure (AA/AG 7.0%, GG 10.6%; p = 0.045) and HR 1.457 (0.919-2.309, p = 0.109); 36 PAD (4.0%; AA/AG 2.3%, GG 5.8%; p = 0.007) with HR 2.225 (1.057-4.684, p = 0.035). No association was found with cerebrovascular events, end stage renal disease, and all-cause mortality.

Conclusions: The rs7896005 SNP of SIRT1 might play a role in cardiovascular disease, mainly CHD risk in T2DM. Results call for larger association studies as well as studies to ascertain mechanisms by which this variant confers increased risk.

Keywords: SIRT1 gene; all-cause mortality; cardiovascular outcomes; observational study; type 2 diabetes.

FIGURE 1

Kaplan‐Meier (K‐M) curves describing the cumulative incidences of major vascular events in subjects stratified by the rs7896005 variant (GG, red line vs. AA/AG, blue line). Percentages of events and Cox proportional unadjusted hazard ratios (HRs, 95% CI) are shown for each group. Panel (A): major cardiovascular (CV) events; panel (B): coronary heart disease (CHD) events; panel (C): hospitalisations for heart failure (HF)

FIGURE 2

Kaplan‐Meier (K‐M) curves describing the cumulative incidences of major vascular events in subjects stratified by the rs7896005 variant (GG, red line vs. AA/AG, blue line). Percentages of events and Cox proportional unadjusted hazard ratio (HR) (HRs, 95% CI) are shown for each group. Panel (A): peripheral artery disease (PAD) events; panel (B): cerebrovascular events; panel (C): end stage renal disease (ESRD)