SIRT1 rs7896005 polymorphism may be related to coronary artery disease in Caucasians with type 2 diabetes, without affecting all-cause mortality.

Background and aims: SIRT1 exerts a number of effects involved in the aging processes and lifespan determination. More recently, SIRT1 has been claimed to be involved in cardiovascular risk as well. The SIRT1 gene is very polymorph with at least 21 SNPs so far identified. Three-four SNPs tag all 21 SNPs with rs10509291 and rs7896005 being nominally associated with type 2 diabetes (T2DM). Less information is available about the relationship between SIRT1 gene variants and diabetic complications. Materials and methods: We have genotyped the rs7896005 (A/G; A is ancestral) SNP, which captures most of the variation across the SIRT1 locus, in 961 T2DM to investigate associations with: 1. the prevalence of micro- and cardiovascular (CVD) complications and 2. all-cause mortality over a median follow-up of 12.3 years (IQR 12.0-12.8). Results: Genotypes distribution was: AA, n. 85 (8.8%); AG, n. 415 (43.2%); GG, n. 461 (48.0%). MAF was 0.3040 and Hardy-Weinberg equilibrium met (p=0.5394). About 10% of the samples were randomly selected for repeated assays with a results concordance of 100%. There was no difference across genotypes for age, diabetes duration (DD), BMI, fasting glucose and HbA1c, blood pressure and lipids, urinary A/C ratio and eGFR (CKD-EPI). Also, there were no differences in genders, active smokers, and family history for diabetes or CVD, prevalence of hyper- tension or dyslipidemia. GG was more frequent among subjects with peripheral polyneuropathy (54.8% vs. 45.8%; p=0.032, Kendall’s test). A similar difference was numerically present between subjects with macro- vs. normo-albuminuria (61.8% vs. 47.3%; p=0.076), with no dif- ference for retinopathy or CKD stage. Myocardial infarction (MI) and any coronary artery disease (CHD; not coronary revascularization procedures) were nominally more frequent in GG homozygous (6.9% and 16.9%, respectively) than in AG (4.1% and 13.3%) and AA homozygous (1.2% and 5.9%; p=0.011 and p=0.010, respectively). Consistently, peripheral artery disease was more common in GG (16.3%) than in AG (11.8%) and in AA (8.2%; p=0.015), with no association with cerebrovascular events. By logistic regression analysis including male gender, age, DD, hyperten- sion, dyslipidemia, retinopathy, A/C ratio strata and CKD stage, GG remained an independent predictor of MI (OR 7.376), and both GG and AG for any CHD (OR 4.102 and 2.865, respectively). Over the 12-year follow-up, all-cause mortality was 19.3% (195 out of 961; M: 124/565, 21.9%; F: 61/396, 15.4%) with no difference among genotypes: AA: 18/ 85, 21.2%; AG: 74/415, 17.8%; GG 93/461, 20.2% (p=0.633). Conclusion: This study suggests that the rs7896005 A/G SNP of SIRT1 might play a role in the risk of coronary artery disease in T2DM, although no association was apparent with all-cause mortality. This results calls for larger association studies as well as studies to ascertain the mechanisms through which this genetic variant could result in increased CHD risk. Supported by: Regione Toscana, Grant n. D55E11002680005