Abstract
Sirtuins (SIRT1-7) are NAD+-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.
Highlights
About 45–50 million people suffer from Alzheimer’s disease (AD) (75 million in 2030; 145 million in 2050; 7.7 million new cases/year)
We report for the first time the genophenotype of patients associated with sirtuin 2 variants and interactions with the apolipoprotein E (APOE) gene, the most relevant pathogenic risk factor for dementia, and with the CYP2D6 gene, the most influential metabolic gene in AD pharmacogenetics [2,3,4,6,19]
In agreement with these results reported by Park et al [181], it appears that cilostazol-stimulated expressions of P-LKB1 and P-AMPKα are SIRT1-dependent
Summary
About 45–50 million people suffer from Alzheimer’s disease (AD) (75 million in 2030; 145 million in 2050; 7.7 million new cases/year). Neurodegenerative disorders share some features in common, including (i) polygenic/complex anomalies, together with epigenetic modifications, cerebrovascular alterations and environmental risk factors; (ii) age-related onset and disease progression (an increase in prevalence in parallel with age); (iii) progressive neuronal degeneration starting in early periods of life with clinical manifestations occurring decades later; (iv) accumulation of abnormal proteins and conformational changes in pathogenic proteins (abnormal deposits of neurotoxic byproducts); (v) no specific biomarkers for a predictive diagnosis and unspecific clinical phenotypes for an early detection; and (vi) limited options for therapeutic intervention with no curative treatments [7]. Classic epigenetic mechanisms include DNA methylation, chromatin remodeling/histone modifications, and microRNA (miRNA) regulation. We report for the first time the genophenotype of patients associated with sirtuin 2 variants (rs10410544) and interactions with the apolipoprotein E (APOE) gene, the most relevant pathogenic risk factor for dementia, and with the CYP2D6 gene, the most influential metabolic gene in AD pharmacogenetics [2,3,4,6,19]. Fatty liver disease; Lymphopenia; Lordokyphosis; Metabolic syndrome; Type 2 diabetes Breast cancer; Leukemia; Lymphomas; Thyroid cancer
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