RESUMEN
Background/Objectives: Corticosteroids are widely used for the treatment of coronavirus disease (COVID)-19 caused by SARS-CoV- 2 as they attenuate the immune response with their antiinflammatory properties. Genetic polymorphisms of glucocorticoid receptor, metabolizing enzymes or transporters may affect treatment response to dexamethasone. The aim of this study was to evaluate the association of polymorphisms in glucocorticoid pathway with disease severity and duration of dexamethasone treatment in COVID-19 patients. Method(s): Our study included 107 hospitalized COVID-19 patients treated with dexamethasone. We isolated DNA from peripheral blood and genotyped all samples for polymorphisms in NR3C1 (rs6198, rs33388), CYP3A4 (rs35599367), CYP3A5 (rs776746), GSTP1 (rs1695, rs1138272), GSTM1/GSTT1 deletions and ABCB1 (1045642, rs1128503, rs2032582 Fisher's and Mann- Whitney tests were used in statistical analysis. Result(s): The median (min-max) age of the included patients was 62 (26-85) years, 69.2 % were male and 30.8 % female and they had moderate (1.9 %), severe (83 %) or critical (15.1 %) disease. NR3C1 rs6198 polymorphism was associated with more severe disease in additive genetic model (P = 0.022). NR3C1 rs6198, ABCB1 rs1045642 and ABCB1 rs1128503 polymorphisms were associated with a shorter duration of dexamethasone treatment in additive (P = 0.048, P = 0.047 and P = 0.024, respectively) and dominant genetic models (P = 0.015, P = 0.048 and P = 0.020, respectively), while carriers of the polymorphic CYP3A4 rs35599367 allele required longer treatment with dexamethasone (P = 0.033). Other polymorphisms were not associated with disease severity or dexamethasone treatment duration. Conclusion(s): Genetic variability of glucocorticoid pathway genes was associated with the duration of dexamethasone treatment of COVID-19 patients.
RESUMEN
Facing SARS-CoV-2 requires rapid development of effective diagnostic and antiviral therapeutic agents. Changes in lipid metabolism have been previously reported during viral infections (e.g. HBV, HCV, HIV), where a specific lipid profile of the host could serve as a biomarker. Besides being a fundamental lipid component of vertebrate cell membranes and participating in numerous physiological processes, cholesterol is being recognized as a molecule involved in regulating SARS-CoV-2 entry. Generally, higher membrane cholesterol coincides with higher efficiency of coronavirus entry, while disruption of cholesterol-enriched lipid rafts by lipid-lowering treatment affects their infectivity. Moreover, studies on COVID-19 patients show decreased levels of serum total cholesterol, HDL-and LDL-cholesterol, but the role of cellular cholesterol synthesis has not yet been thoroughly investigated. Herein we focus on serum cholesterol and its intermediates in patients hospitalized due to COVID-19. Samples were taken at three-time points during hospitalization, to contrast the disease severity in individual patient. We aim to evaluate whether the sterol-related biomarkers can be used for the prediction of the disease progression or outcome and whether the cholesterol and its sterol intermediates affect the entry of SARSCoV-2. Initial results indicate that cholesterol precursors (i.e. lathosterol) correlate with COVID-19 severity in the Slovenian cohort. The analysis of the targeted cholesterol-related RNAs from patients' serum is in progress. The role of cholesterol and other sterols in SARS-CoV-2 spike protein interaction is studied in immortal cell lines with impaired cholesterol synthesis. Uncovering to which extend the blood and membrane-bound cholesterol imbalance relates to COVID-19 pathology will give valuable insight also regarding the suitability of treatment of patients with lipid-lowering drugs.