Farmacogenética de reacciones adversas a fármacos antiepilépticos

PLANTEAMIENTO:Las reacciones adversas a medicamentos (RAM) son un problema de salud pública y una importante causa de morbimortalidad a nivel mundial. En el caso de los fármacos antiepilépticos (FAE), la presencia de RAM puede ser un impedimento para lograr el éxito terapéutico al dificultar la adherencia al tratamiento e impactar la calidad de vida del paciente. La farmacogenética busca la identificación de variantes genéticas asociadas a la seguridad de los fármacos. En este artículo se revisan los genes que codifican para enzimas metabolizadoras y transportadores de fármacos, así como en el sistema HLA asociados a RAM inducidas por FAE. DESARROLLO: A la fecha, se ha reportado la asociación de los alelos CYP2C9*2 y *3, que codifican para enzimas de actividad reducida, con efectos neurotóxicos por fenitoína (PHT); alelos nulos de GSTM1 asociados con hepatotoxicidad inducida por carbamazepina (CBZ) y ácido valproico (VPA); polimorfismos genéticos de EPHX1 en la teratogénesis inducida por PHT; variantes genéticas de ABCC2 asociadas con RAM neurológicas por CBZ y VPA, y también diversos alelos de HLA (p. ej., HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) asociados con RAM de tipo cutáneas. CONCLUSIONES: Los hallazgos publicados muestran que existen RAM con base farmacogenética con una alta variabilidad interétnica, lo que refleja la necesidad de que se realicen estudios en distintas poblaciones para poder obtener resultados que sean de utilidad a un número mayor de pacientes. La búsqueda de biomarcadores que permitan la predicción de RAM a FAE podría mejorar la farmacoterapia en la epilepsia.BACKGROUND: Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients’ quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. DEVELOPMENT: To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. CONCLUSIONS: Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy.• Consejo Nacional de Ciencia y Tecnología (México). Subvención #167261 • Consejo Nacional de Ciencia y Tecnología (México). Subvención #369708, para investigación doctoral de Ingrid Fricke GalindopeerReviewe

IFNAR2 relevance in the clinical outcome of individuals with severe COVID-19

Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel

SERPINE1 rs6092 Variant Is Related to Plasma Coagulation Proteins in Patients with Severe COVID-19 from a Tertiary Care Hospital

An impaired coagulation process has been described in patients with severe or critical coronavirus disease (COVID-19). Nevertheless, the implication of coagulation-related genes has not been explored. We aimed to evaluate the impact of F5 rs6025 and SERPINE1 rs6092 on invasive mechanical ventilation (IMV) requirement and the levels of coagulation proteins among patients with severe COVID-19. Four-hundred fifty-five patients with severe COVID-19 were genotyped using TaqMan assays. Coagulation-related proteins (P-Selectin, D-dimer, P-selectin glycoprotein ligand-1, tissue plasminogen activator [tPA], plasminogen activator inhibitor-1, and Factor IX) were assessed by cytometric bead arrays in one- and two-time determinations. Accordingly, SERPINE1 rs6092, P-Selectin (GG 385 pg/mL vs. AG+AA 632 pg/mL, p = 0.0037), and tPA (GG 1858 pg/mL vs. AG+AA 2546 pg/mL, p = 0.0284) levels were different. Patients carrying the CT F5-rs6025 genotype exhibited lower levels of factor IX (CC 17,136 pg/mL vs. CT 10,247 pg/mL, p = 0.0355). Coagulation proteins were also different among IMV patients than non-IMV. PSGL-1 levels were significantly increased in the late stage of COVID-19 (>10 days). The frequencies of F5 rs6025 and SERPINE1 rs6092 variants were not different among IMV and non-IMV. The SERPINE1 rs6092 variant is related to the impaired coagulation process in patients with COVID-19 severe

The rs16969968 Tobacco Smoking-Related Single-Nucleotide Variant Is Associated with Clinical Markers in Patients with Severe COVID-19

Tobacco smoking is the leading risk factor for many respiratory diseases. Several genes are associated with nicotine addiction, such as CHRNA5 and ADAM33. This research aims to evaluate the association of the polymorphisms rs16969968 (CHRNA5) and rs3918396 (ADAM33) in patients who developed severe COVID-19. We included 917 COVID-19 patients hospitalized with critical disease and oxygenation impairment. They were divided into two groups, tobacco-smoking (n = 257) and non-smoker (n = 660) patients. The genotype and allele frequencies of two single nucleotide variants, the rs16969968 (CHRNA5) and rs3918396 (ADAM33), were evaluated. The rs3918396 in ADAM33 does not show a significative association. We analyzed the study population according to the rs16969968 genotype (GA + AA, n = 180, and GG, n = 737). The erythrocyte sedimentation rate (ESR) shows statistical differences; the GA + AA group had higher values than the GG group (p = 0.038, 32 vs. 26 mm/h, respectively). The smoking patients and GA or AA genotype carriers had a high positive correlation (p < 0.001, rho = 0.753) between fibrinogen and C-reactive protein. COVID-19 patients and smokers carriers of one or two copies of the risk allele (rs16969968/A) have high ESR and a positive correlation between fibrinogen and C-reactive protein

Genetic variants in ATP2B2 as risk factors for mortality in patients unrelated but not associated with families with severe COVID-19

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has a wide range of clinical manifestations, from asymptomatic to severe. Ancestral contribution, sex, immune response, and genetic factors influence the presentation of the disease. The objective of the present study was to validate these genetic variants in patients with severe COVID-19 who died and in survivor patients. Methods: Single nucleotide variants (SNVs) in six genes: ATPase plasma membrane Ca2+ transporting 2 (ATP2B2), transmembrane serine protease 2 (TMPRSS2), dedicator of cytokinesis 2 (DOCK2), (interferon alpha and beta receptor subunit 2) IFNAR2, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), were explored in two groups: the first consisted of severe COVID-19-related patients (familial cases from 58 families, n = 130), and the second group of unrelated severe COVID-19 patients (n = 1045). In each study group, death was evaluated as the outcome. Results: In non-related patients with severe COVID-19, carriers of GG genotype (rs2289274) in the ATP2B2 gene showed a high-risk probability of non-surviving (OR = 1.43). Survival analysis to 75 days indicates that carriers of GG have a higher risk than GA or AA genotypes (p = 0.0059). The haplotype GG (rs2289273-rs2289274) in ATP2B2 was found to be associated with a high risk of death in severe non-related COVID-19 patients. No significant associations were found between severe COVID-19-related patients and SNVs in ATP2B2, TMPRSS2, DOCK2, IFNAR2, TNFRSF1A, or TNFRSF1B. Conclusions: Unrelated patients with severe COVID-19 that carry the GG genotype (rs2289274) in ATP2B2 showed a high death risk. Survival analysis to 75 days indicates that carriers of GG have a higher risk of non-survival compared to GA or AA genotypes

The <i>ACE</i> rs1799752 Variant Is Associated with COVID-19 Severity but Is Independent of Serum ACE Activity in Hospitalized and Recovered Patients

This paper assesses the association of the insertion/deletion ACE (angiotensin-converting enzyme) variant (rs1799752 I/D) and the serum ACE activity with the severity of COVID-19 as well as its impact on post-COVID-19, and we compare these associations with those for patients with non-COVID-19 respiratory disorders. We studied 1252 patients with COVID-19, 104 subjects recovered from COVID-19, and 74 patients hospitalized with a respiratory disease different from COVID-19. The rs1799752 ACE variant was assessed using TaqMan® Assays. The serum ACE activity was determined using a colorimetric assay. The DD genotype was related to risk for invasive mechanical ventilation (IMV) requirement as an indicator of COVID-19 severity when compared to the frequencies of II + ID genotypes (p = 0.025, OR = 1.428, 95% CI = 1.046–1.949). In addition, this genotype was significantly higher in COVID-19 and post-COVID-19 groups than in the non-COVID-19 subjects. The serum ACE activity levels were lower in the COVID-19 group (22.30 U/L (13.84–32.23 U/L)), which was followed by the non-COVID-19 (27.94 U/L (20.32–53.36 U/L)) and post-COVID-19 subjects (50.00 U/L (42.16–62.25 U/L)). The DD genotype of the rs1799752 ACE variant was associated with the IMV requirement in patients with COVID-19, and low serum ACE activity levels could be related to patients with severe disease

High Expression Levels of miR-21-5p in Younger Hospitalized COVID-19 Patients Are Associated with Mortality and Critical Disease

In COVID-19, critical disease and invasive mechanical ventilation (IMV) increase the risk of death, mainly in patients over 60 years of age. Objectives: To find the relationship between miR-21-5p and miR-146a-5p in terms of the severity, IMV, and mortality in hospitalized COVID-19 patients younger than 55 years of age. Methods: The patients were stratified according to disease severity using the IDSA/WHO criteria for severe and critical COVID-19 and subclassified into critical non-survivors and critical survivors. Results: Ninety-seven severe/critical COVID-19 patients were included; 81.3% of the deceased were male and 18.8% were female. Higher expression miR-21-5p levels were associated as follows: severe vs. critical disease (p = 0.007, FC = 0.498), PaO2/FiO2 index, mild vs. severe (p = 0.027, FC = 0.558), and survivors vs. non-survivors (p = 0.03, FC = 0.463). Moreover, we identified correlations with clinical variables: CRP (rho = −0.54, p p p p p < 0.001). Finally, miR-21-5p thresholds were calculated according to severity (8.191), IMV (8.191), and mortality (8.237); these values increased the risk of developing a critical disease (OR = 4.19), the need for IMV (OR = 5.63), and death (OR = 6.00). Conclusion: Increased expression levels of miR-21-5p are related to worse outcome of COVID-19 in younger hospitalized patients