Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

Carril

et al. 2019

IJMS

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.

Section: Pharmacoepigenetics Of Sirtuin Modulators and Epigenetic mentioning

confidence: 99%

Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics

Carril

et al. 2019

IJMS

“…As it is well recognised that there are ethnicspecific genetic and epigenetic patterns, as well as associations with health outcomes, this must be considered as one possible reason for the discrepancy in findings between studies (e.g. in Asian versus Caucasian populations) [58,59].…”

Section: Discussionmentioning

confidence: 99%

Is Peripheral BDNF Promoter Methylation a Preclinical Biomarker of Dementia?

Fransquet

Ritchie

Januar

et al. 2020

JAD

Brain derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14-years. BDNF exon 1 promoter methylation was measured in blood at baseline (n=769), and buccal samples during follow-up (n=1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE-ɛ4. Multivariable logistic regression analyses determined the association between BDNF methylation and both prevalent and incident dementia. Adjustment for gender, age, education, APOE-ε4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ-0.5%, 95%CI:-0.9,-0.04, p=0.03, p=0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p=0.02, p=0.14 adjusted and Δ-1.5%, OR:0.85, SE:0.06, p=0.03, p=0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r=-0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing.

“…Analyzing the results, we can assume reduced methylation in the promoter regions of LAMP2 in cancer with respect to the control. BECN1 is silenced in cancer tissue, which indicates that DNA methylation may also be responsible for this mechanism [55][56][57]. There are not many studies on the expression of PINK1 in cancer.…”

Section: Discussionmentioning

confidence: 99%

The Expression Patterns of BECN1, LAMP2, and PINK1 Genes in Colorectal Cancer Are Potentially Regulated by Micrornas and CpG Islands: An In Silico Study

Bednarczyk

Fatyga

Dzięgielewska-Gęsiak

et al. 2020

JCM

Background: Autophagy plays a dual role of tumor suppression and tumor promotion in colorectal cancer. The study aimed to find those microRNAs (miRNAs) important in BECN1, LAMP2, and PINK1 regulation and to determine the possible role of the epigenetic changes in examined colorectal cancer using an in silico approach. Methods: A total of 44 pairs of surgically removed tumors at clinical stages I‒IV and healthy samples (marginal tissues) from patients’ guts were analyzed. Analysis of the obtained results was conducted using the PL-Grid Infrastructure and Statistica 12.0 program. The miRNAs and CpG islands were estimated using the microrna.org database and MethPrimer program. Results: The autophagy-related genes were shown to be able to be regulated by miRNAs (BECN1—49 mRNA, LAMP2—62 mRNA, PINK1—6 mRNA). It was observed that promotion regions containing at least one CpG region were present in the sequence of each gene. Conclusions: The in silico analysis performed allowed us to determine the possible role of epigenetic mechanisms of regulation gene expression, which may be an interesting therapeutic target in the treatment of colorectal cancer.