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Sulfonylureas are insulin secretagogues which act in pancreatic β cells by blocking the KATP channels encoded by KCNJ11 and ABCC8 genes. In the present study, a pharmacoepigenetic approach was applied for the first time, investigating the correlation of KCNJ11 and ABCC8 gene promoter methylation with sulfonylureas-induced mild hypoglycemic events as well as the KCNJ11 E23K genotype. Sodium bisulfite-treated genomic DNA of 171 sulfonylureas treated T2DM patients previously genotyped for KCNJ11 E23K, including 88 that had experienced drug-associated hypoglycemia and 83 that had never experienced hypoglycemia, were analyzed for DNA methylation of KCNJ11 and ABCC8 gene promoters via quantitative Methylation-Specific PCR. KCNJ11 methylation was detected in 19/88 (21.6%) of hypoglycemic and in 23/83 (27.7%) of non-hypoglycemic patients (p=0.353), while ABCC8 methylation in 6/83 (7.2%) of non-hypoglycemic and none (0/88) of the hypoglycemic patients (p=0.012). Methylation in at least one promoter (KCNJ11 or ABCC8) was significantly associated with non-hypoglycemic patients who are carriers of KCNJ11 EK allele (p=0.030). Our data suggest that ABCC8 but not KCNJ11 methylation is associated to hypoglycemic events in sulfonylureas-treated T2DM patients. Furthermore, it is demonstrated that the KCNJ11 E23K polymorphism in association to either of the two genes' DNA methylation may have protective role against sulfonylurea-induced hypoglycemia. [ABSTRACT FROM AUTHOR]

Genetic factors are considered to play an important role in determining the susceptibility to the occurrence, clinical course, and functional outcome of an acute ischemic stroke (IS). Undercarboxylation of specific vitamin K-dependent proteins, due to genetic polymorphisms of VKORC1, can affect both vascular calcification and thrombogenicity. We sought to determine the association of VKORC1 -1639G > A polymorphism with IS incidence, age of onset, severity of disease, and functional outcome after an acute IS. VKORC1 -1639G > A polymorphism was determined in 145 consecutive patients with first ever IS and 145 age- and sex-matched control subjects of Greek Caucasian origin using PCR-RFLP. Stroke severity and functional outcome were assessed on admission and at one month after stroke, respectively. Frequency of VKORC1 -1639G > A genotypes did not differ between IS patients and controls (OR = 1.12, P = 0.51). Moreover, carriage of the A allele was not associated with age of stroke onset, severity of disease (Scandinavian stroke scale score 32.2 versus 32.9, resp., P = 0.96), or poor outcome at 1 month post-stroke (52.9 versus 64.4%, resp., P = 0.31). In conclusion, VKORC1 -1639G > A polymorphism is not a genetic determinant of IS occurrence, age of onset, severity, or functional outcome of disease in a Greek population. [ABSTRACT FROM AUTHOR]

Polymorphisms in the genes encoding CYP2C9 enzyme and VKORC1 reductase significantly influence the dose variability of coumarinic oral anticoagulants (COAs). Substantial inter- and intraethnic variability exists in the frequencies of CYP2C9*2 and *3 and VKORC1 -1639A alleles. However, the prevalence of CYP2C9 and VKORC1 genetic variants is less characterized in Arab populations. A total of 131 healthy adult subjects from the Al-Ahsa region of Saudi Arabia were genotyped for the CYP2C9*2 and *3 and VKORC1 -1639G>A polymorphisms by PCR-RFLP method. The frequencies of the CYP2C9*2 and *3 and VKORC1 -1639A alleles were 13.3%, 2.3%, and 42.4%, respectively, with no subjects carrying 2 defective alleles. The frequencies of the CYP2C9*3 and VKORC1 -1639A alleles were significantly lower than those reported in different Arabian populations. None of the subjects with the VKORC1 -1639AA genotype were carriers of CYP2C9*1/*3 genotypes that lead to sensitivity to COAs therapy. The low frequency of the CYP2C9*3 allele combined with the absence of subjects carrying 2 defective CYP2C9 alleles suggests that, in this specific population, pharmacogenetic COAs dosing may mostly rely upon VKORC1 genotyping. [ABSTRACT FROM AUTHOR]

Aim: MicroRNA 27a (miR-27a) regulates post-transcriptionally DPD activity. We have analyzed the association of MIR27A rs895819T>C variation, that modulates miR-27a expression, with fluropyrimidine-induced toxicity. Materials & methods: MIR27A rs895819T>C genotyping was conducted by TaqMan® allelic discrimination assay in 313 FP-treated cancer patients. Results: In overdominance (TC vs TT + CC), TC genotype was associated with grade 3-4 toxicity (p = 0.002), any grade toxicity (p = 0.052), and delayed drug administration or therapy discontinuation (p = 0.038). Odds of grade 3-4 toxicity were increased by both DPYD deficiency (OR: 8.923; p = 0.006) and MIR27A rs895819 TC genotype (OR: 3.865; p = 0.002). Conclusion: MIR27A rs895819 TC genotype is an independent risk factor for fluoropyrimidine-associated toxicity in the Greek population. Thus, MIR27A rs895819TC patients can be closely monitored for fluoropyrimidine-induced severe toxicity.

COVID-19 is a systemic disease affecting tissues and organs, including and beyond the lung. Apart from the current pandemic context, we also have vastly inadequate knowledge of consequences of repeated exposures to SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, in multiple organ systems and the whole organism scales when the disease evolves from a pandemic to an endemic state. This calls for a systems biology and systems medicine approach and unpacking the effects of COVID-19 in lung as well as other tissues. We report here original findings from transcriptomics analyses and differentially expressed genes (DEGs) in lung samples from 60 patients and 27 healthy controls, and in whole blood samples from 255 patients and 103 healthy individuals. A total of 11 datasets with RNA-seq transcriptomic data were obtained from the Gene Expression Omnibus and the European Nucleotide Archive. The identified DEGs were used to construct protein interaction and functional networks and to identify related pathways and miRNAs. We found 35 DEGs common between lung and the whole blood, and importantly, 2 novel genes, namely CYP1B1 and TNFAIP6 , which have not been previously implicated with COVID-19. We also identified four novel miRNA potential regulators, hsa-mir-192-5p, hsa-mir-221-3p, hsa-mir-4756-3p, and hsa-mir-10a-5p, implicated in lung or other diseases induced by coronaviruses. In summary, these findings offer new molecular leads and insights to unpack COVID-19 systems biology in a whole organism context and might inform future antiviral drug, diagnostics, and vaccine discovery efforts.

Obstructive sleep apnea syndrome (OSAS) is a multifactorial and common disorder affecting 10-17% of men and 3-9% of women. A low vitamin D serum concentration has been reportedly linked to OSAS susceptibility, but the underlying molecular genetic mechanisms are poorly understood thus far. We report here original findings on the ways in which vitamin D receptor (VDR) gene polymorphic variation (FokI, BsmI, ApaI, and TaqI polymorphisms) impacts serum vitamin D concentration and, additionally, susceptibility to OSAS. In a sample of 176 consecutive subjects (144 patients with OSAS and 32 healthy controls) phenotyped by full polysomnography (PSG), we characterized human genetic variation in VDR using the Sequenom MassARRAY iPLEX platform. A logistic regression analysis was employed to account and correct for covariates such as sex, age, body mass index, and comorbidities. Importantly, we observed that the FokI CC genotype frequency was markedly higher in patients with OSAS compared with controls (50.7% vs. 28.1%; p = 0.027). VDR FokI polymorphism explained 14.5% of vitamin D serum concentration variability. Moreover, the VDR FokI polymorphism was also associated with excessive daytime sleepiness (p = 0.016). To the best of our knowledge, this is the first clinical genetics study examining the role of VDR polymorphic variation on OSAS as phenotyped using full PSG. We call for further studies of vitamin D-related mechanisms that might contribute to OSAS risk in independent populations.

Coronary artery disease (CAD) is a major global health burden whereby gene-by-environment-by-sex interactions play an important role. Coronary artery bypass graft (CABG) surgery involves patients with well-documented and severe CAD. Hence, the study of CAD in a context of the CABG surgery serves as an advantageous model for disease phenotype ascertainment and genetic association studies. We report here new observations from a case-control genetic association study on promoter methylation of the cystathionine γ-lyase (CTH) gene and its association with CAD. To the best of our knowledge, this is the first clinical study to show the DNA methylation status of the CTH promoter in relation to this clinical phenotype. CTH encodes for the hydrogen sulfide generating enzyme named CSE in the endothelium that is mechanistically highly relevant for CAD. In a sample of 334 subjects from Greece (178 cases with CAD and who underwent CABG, and 156 controls), CTH promoter methylation was analyzed using a SYBR Green-based quantitative methylation-specific polymerase chain reaction. We found increased methylation in CTH promoter in cases (19.1%) compared to controls (10.3%) (p = 0.024). Gene-by-sex analysis sustained the significant association in men (p = 0.032) but not in women (p = 0.884). By using multivariate analyses after controlling for potential confounders such as smoking, age, and gender, we found that increased CTH gene promoter methylation was associated with CAD in the total sample (odds ratio [OR] = 2.163, 95% confidence interval [CI] 1.038-4.506, p = 0.039) and in men (OR = 2.418, 95% CI 1.048-5.581, p = 0.039) but not in women (OR = 0.542, 95% CI 0.094-3.140, p = 0.495). These observations collectively warrant further precision medicine and biomarker research to examine the CTH methylation status as a putative epigenetic regulator of CAD risk in larger and independent samples.

Background: The reinforcing effects of alcohol are mediated through complex interactions between multiple neurochemical systems. Genes of dopaminergic (DRD2, DRD3 and DβH), opioid (OPRM1) and glutaminergic (GRIK1) systems mediate the dependent behavior via different mechanisms; however, they all target the serotonergic and dopaminergic pathways in the ventral tegmental area., Methods: In the present study, DRD2 A2/A1, DRD3 Ser9Gly, DβH -1021C>T, OPRM1 A118G and GRIK1 rs2832407C>A polymorphisms and their interactions were analyzed in 72 alcohol-dependent patients and 74 controls of Greek-Cypriot origin, using the PCR-RFLP method., Results: No differences were found in the genotype or allele distribution of DRD2 A2/A1, DRD3 Ser9Gly, DβH -1021C>T, OPRM1 A118G and GRIK1 rs2832407C>A between alcohol-dependent patients and controls. Additionally, we did not find any gene×gene interactions in association with alcohol dependence in the studied population., Conclusions: Alcohol dependence is a complex interaction of genetic and environmental factors. In the present study, we have shown that DRD2 A2/A1, DRD3 Ser9Gly, DβH -1021C>T, OPRM1 A118G and GRIK1 rs2832407C>A are not associated with this dependent behavior alone or in interaction.