ABSTRACT
BACKGROUND: Oxidative stress and inflammation are major drivers of myocardial hypertrophy in chronic kidney disease (CKD). The silent information regulator gene 1 (Sirt1) is a fundamental mediator of the response to oxidative stress and inflammation and promotes myocardial growth under stress conditions; therefore, it may contribute to myocardial hypertrophy and concentric remodeling of the left ventricle (LV) in CKD. METHODS: We investigated the cross-sectional and longitudinal relationship between three candidate polymorphisms in the Sirt1 gene and LV parameters in two cohorts of CKD patients including 235 stage G5D patients and 179 stages G1-5 patients, respectively. RESULTS: In both cohorts, the C allele of the Sirt1 rs7069102 polymorphism associated with the posterior wall thickness in separate and combined analyses (betaâ=â0.15, Pâ=â2â×â10) but was unrelated with the LV volume and the LV mass index indicating a peculiar association of this allele with LV concentric remodeling. Accordingly, the same allele was linked with the LV mass-to-volume ratio in separate and combined (betaâ=â0.14, Pâ=â2â×â10) analyses in the same cohorts. Furthermore, in longitudinal analyses patients harboring the C allele showed a more pronounced increase in LV mass-to-volume ratio over time than patients without such an allele (regression coefficientâ=â0.14, 95% confidence interval: 0.05-0.23; Pâ=â3â×â10 in the combined analysis). CONCLUSION: The rs7069102 polymorphism in the Sirt1 gene is associated with LV concentric remodeling in two independent cohorts of stages G5D and G1-5 CKD patients. These results offer a genetic basis to the hypothesis that the Sirt1 gene plays a causal role in myocardial hypertrophy and LV concentric remodeling in these patients.
Subject(s)
Hypertrophy, Left Ventricular/genetics , Renal Insufficiency, Chronic/complications , Sirtuin 1/genetics , Ventricular Remodeling/genetics , Adult , Aged , Alleles , Cross-Sectional Studies , Female , Humans , Hypertrophy, Left Ventricular/etiology , Kidney Failure, Chronic/complications , Longitudinal Studies , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Polymorphisms in the FTO (fat-mass and obesity-associated) gene have been associated with the body mass index, cancer, type 2 diabetes and hypertension. METHODS: We investigated the relationship between 17 tag single-nucleotide polymorphisms (SNPs) and all-cause mortality in three cohorts of dialysis patients (CREED-1, North Apulian and CREED-2 cohorts; n = 783) and in one cohort of stage 2-5 CKD patients (n = 757). RESULTS: We first explored the association between the 17 tag SNPs and all-cause mortality in the CREED-1 cohort and found that patients with the A allele of the FTO rs708259 polymorphism had an elevated risk of mortality (hazard ratio, HR: 1.52, 95% confidence interval (CI) 1.11-2.08; P = 0.008). Similarly, the A allele was associated with an increased risk of death also in the other two dialysis cohorts (North Apulian cohort, risk: +23%; CREED-2 cohort, risk: +21%). The elevated risk portended by this allele was even higher in the stage 2-5 CKD cohort (+97%). However, the risk of mortality associated with the A allele in the three confirmatory cohorts failed to achieve formal statistical significance. In a meta-analysis including the four cohorts (n = 1540; total deaths, n = 381), individuals with the A allele had a 42% excess risk of death (HR: 1.42, 95% CI 1.14-1.76, P = 0.002). CONCLUSION: The A allele of the FTO rs708259 polymorphism is an independent predictor of all-cause mortality in patients with CKD of various severity. These data support our hypothesis that the FTO gene may be a relevant genetic risk factor for mortality in this population.