Pharmacogenetics of adverse reactions to antiepileptic drugs

Introduction: 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. Resumen: Introducción: 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. Keywords: Pharmacogenetics, Adverse drug reactions, Antiepileptic drugs, CYP2C9, ABCC2, Human leukocyte antigen (HLA), Palabras clave: Farmacogenética, Reacciones adversas a medicamentos, Fármacos antiepilépticos, CYP2C9, ABCC2, Antígeno leucocitario humano (HLA

Diagnostic accuracy of prenatal ultrasound in coarctation of aorta: systematic review and individual participant data meta-analysis

objective: to determine the diagnostic accuracy of prenatal ultrasound (US) in detecting coarctation of aorta (CoA). methods: an individual participant data meta-analysis was performed to report the strength of association and diagnostic accuracy of different US signs in detecting CoA prenatally. MEDLINE, embase, and CINAHL were searched from January 2000 until november 2021. Individual participant-level data was obtained by two leading teams. PRISMA-IPD and PRISMA-DTA guidelines were used for abstracting data and the QUADAS-2 tool for assessing quality and applicability. the reference standard was CoA diagnosed after birth defined as narrowing of the aortic arch. the index test included the most commonly evaluated parameters on US both in B-mode and doppler. summary estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and likelihood ratios were computed using hierarchical summary receiver-operating characteristics. results: the initial search yielded 72 studies of which 25 met the inclusion criteria (evaluation of fetuses with suspected CoA considered as isolated cardiac and/or great vessels disproportion with right dominance on US assessment). seventeen studies (640 fetuses) were included. at random effect logistic regression analysis, tricuspid/mitral valve ratio > 1.4 and >1.6, aortic isthmus/arterial duct ratio <0.7, hypoplastic arch (all p<0.001), aortic isthmus z-score <2 at sagittal (p=0.003) and 3-vessel view (p<0.001), pulmonary artery/ascending aorta ratio (p=0.048), bidirectional flow at the foramen ovale (p=0.012) and redundant foramen ovale (p=0.037) were independently associated with CoA. regarding diagnostic accuracy, tricuspid/mitral valve ratio >1.4 had a sensitivity of 72.6% (95%CI, 48.2-88.3), a specificity of 65.4% (95%CI, 46.9-80.2), and a DOR of 5.02 (95%CI, 1.82-13.9). the respective sensitivity/specificity figures for pulmonary artery/ascending aorta ratio >1.4, aortic isthmus z-score <-2 at sagittal and aortic isthmus at 3-vessel views were 75.0% (95%CI, 61.1-86.0)/39.7% (95%CI, 27.0-53.4), 47.8% (95%CI, 14.6-83.0)/87.6% (95%CI, 27.3-99.3) and 74.1% (95%CI, 58.0-85.6)/62.0% (95%CI, 41.6-78.9). Hypoplastic arch had a sensitivity of 70.0% (95%CI, 42.0-88.6), a specificity of 91.3 (95%CI, 78.6-96.8), and a DOR of 24.9 (95%CI, 6.18-100). continuous parameters were independently associated with CoA (all, p<0.001) but all had low-moderate diagnostic yield, same as multivariate models. Conclusions: Several prenatal ultrasound parameters are associated with an increased risk for postnatal CoA. however, diagnostic accuracy is only moderate, even when combined. this article is protected by copyright. all rights reserved

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