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T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for the 55.6%. Patients with A/A and A/G TLR4 genotypes showed significant differences in complication's prevalence. In particular, AG carriers had higher risk prevalence for neuropathy (p = 0.026), lower limb arteriopathy (p = 0.013), and the major cardiovascular pathologies (p = 0.017). Their cumulative risk was significant (p = 0.01), with a threefold risk to develop neuropathy, lower limb arteriopathy, and major cardiovascular events in AG cases compared to AA cases. The adjusted OR for the confounding variables was 3.788 (95% CI: 1.642-8.741).Thus, the rs4986790 polymorphism may be an indicative of prevalence of complications in T2DM patients. [ABSTRACT FROM AUTHOR]

Tumor suppressor protein p53 has been demonstrated to regulate genes involved in energy generating metabolic pathways and apoptosis. To date, a new field of research is the involvement of TP53 codon 72 (Arg72Pro) polymorphism in the diabetic disease. The aim of this study was to evaluate whether the genotype and the related genetic models of Arg72Pro polymorphism of TP53 (rs1042522) are associated with insulin resistance and its metabolic parameters in diabetic and non-diabetic subjects. We examined 335 type 2 diabetic patients (65.5 ± 8.4 years) and 367 non-diabetic subjects (60.5 ± 11.7 years). The results were validated in a validation sample consisting of 199 type 2 diabetic (66.2 ± 8.5 years) and 224 non-diabetic subjects (61.2 ± 12.7 years). In the study sample, the analysis of covariance, adjusted for the effects of age, gender and BMI, showed a significant genotype-diabetes effect on insulin resistance evaluated by HOMA-IR ( p = 0.038). This result was mediated by variations in fasting plasma insulin ( p = 0.027), as no TP53 genotype-diabetes effects were detected for fasting plasma glucose. In particular, in the diabetic subjects, Pro/Pro genotype was associated with lower values of HOMA-IR with respect to Arg/Arg ( p = 0.013) and Arg/Pro ( p = 0.006) carriers. No difference in HOMA-IR between diabetic and non-diabetic Pro/Pro carriers was found. Significant recessive model-diabetes interaction effects on fasting insulin and HOMA-IR adjusted for age, sex and BMI were found ( p = 0.007 and p = 0.029, respectively). Linear regression analyses, based on the assumption of an additive genetic model adjusted for age, sex and BMI, highlight p53 gene-diabetes interaction effects on fasting insulin ( β = −1.27; p = 0.001) and HOMA-IR ( β = −0.22; p = 0.006). The results of statistical analyses on fasting insulin and HOMA-IR were all confirmed in the validation sample. Furthermore, the logistic regression models confirmed that the effect of HOMA-IR levels on diabetes was moderated by Pro/Pro genotype in both study and validation samples (OR = 0.29, p = 0.034, 95 % CI = 0.09-0.91, OR = 0.37, p = 0.035, 95 % CI = 0.15-0.93, respectively). Our findings suggest that p53 codon 72 (Arg72Pro) polymorphism influences insulin resistance in type 2 diabetic patients independently of body mass. [ABSTRACT FROM AUTHOR]

Abstract: Background: Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are key mediators of inflammation and their increased plasma levels are associated with acute coronary syndrome (ACS). Polymorphisms in the promoter region of IL-6 (−174 G>C) and TNF-α (−308 G>A) demonstrated to affect gene expression were analyzed to test their predictive power for cardiovascular death over one year follow-up in elderly male ACS patients. Methods: We assessed the IL-6 −174 G>C polymorphism and TNF-α −308 G>A polymorphism in 139 consecutive elderly male patients affected by an ACS, such as ST-Elevation (STEMI), No ST-Elevation (NSTEMI) Myocardial Infarction and Unstable Angina. The presence of well known risk factors for Coronary Heart Diseases (CHD) were also assessed in all ACS patients. Survival rate was assessed after one year follow-up. Results: We found that IL-6 −174 G>C polymorphism is an independent predictor of cardiovascular death after an ACS in male patients. In particular ACS patients carrying the IL-6 −174 C− (GG) genotypes showed a marked increase in one year follow-up mortality rate (HR=3.89, 95% CI 1.71–8.86, p=0.001). Moreover CRP serum levels ≥5.5 mg/dl (HR= 3.79, 95% CI 1.71–8.42, p=0.001), a history of CHD (HR=2.96, 95% CI 1.22–7.20, p=0.016) and the absence of statins treatment (HR=3.27, 95% CI 1.17–9.18, p=0.021), significantly increased one year risk of death in male ACS patients. Conclusions: These data suggest that IL-6 −174 G>C polymorphism can be added to other clinical markers in order to identify a subgroup of elderly ACS male patients at higher risk of death. [Copyright &y& Elsevier]