RESUMEN
Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5 × 10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.
Asunto(s)
Estudio de Asociación del Genoma Completo , Metoprolol , Humanos , Metoprolol/uso terapéutico , Metoprolol/farmacocinética , Citocromo P-450 CYP2D6/genética , Farmacogenética , Estudios TransversalesRESUMEN
We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10-8) in interaction with colchicine (P = 1.19 × 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Colchicina/uso terapéutico , Estudio de Asociación del Genoma Completo , Adulto , COVID-19/genética , COVID-19/patología , COVID-19/virología , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 9/genética , Método Doble Ciego , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Efecto Placebo , Modelos de Riesgos Proporcionales , Inducción de Remisión , Factores de Riesgo , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la EnfermedadRESUMEN
We sought to perform a genomic evaluation of the risk of incident cancer in statin users, free of cancer at study entry. Patients who previously participated in two phase IV trials (TNT and IDEAL) with genetic data were used (npooled = 11,196). A GWAS meta-analysis using Cox modeling for the prediction of incident cancer was conducted in the pooled cohort and sex-stratified. rs13210472 (near HLA-DOA gene) was associated with higher risk of incident cancer amongst women with prevalent coronary artery disease (CAD) taking statins (hazard ratio [HR]: 2.66, 95% confidence interval [CI]: 1.88-3.76, P = 3.5 × 10-8). Using the UK Biobank and focusing exclusively on women statin users with CAD (nfemale = 2952), rs13210472 remained significantly associated with incident cancer (HR: 1.71, 95% CI: 1.14-2.56, P = 9.0 × 10-3). The association was not observed in non-statin users. In this genetic meta-analysis, we have identified a variant in women statin users with prevalent CAD that was associated with incident cancer, possibly implicating the human leukocyte antigen pathway.
Asunto(s)
Antígenos HLA/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Anciano , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/genética , Femenino , Variación Genética/genética , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2.68 × 10-5, P = 5.81 × 10-4, and P = 5.94 × 10-4, respectively). Required doses of warfarin were the highest for homozygotes of the minor allele at the VDR variants (P < 0.0026). Variants in the VDR gene were associated with the variability in response to warfarin, emphasizing the possible clinical relevance of nuclear receptor gene variants on the inter-individual variability in drug metabolism.
Asunto(s)
Coagulación Sanguínea/genética , Estudio de Asociación del Genoma Completo , Receptores de Calcitriol/genética , Warfarina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Receptor de Androstano Constitutivo , Citocromo P-450 CYP2C9/genética , Relación Dosis-Respuesta a Droga , Receptor alfa de Estrógeno/genética , Femenino , Factor de Transcripción GATA4/genética , Genotipo , Factor Nuclear 4 del Hepatocito/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptor X de Pregnano/genética , Quebec/epidemiología , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Glucocorticoides/genética , Receptor alfa X Retinoide/genética , Vitamina K/genética , Vitamina K/metabolismo , Warfarina/administración & dosificación , Warfarina/efectos adversosRESUMEN
AIM: To optimally address the interindividual variability observed in pharmacokinetic drug response, we have created a custom genotyping panel that interrogates most of the key genetic variations present in a set of 181 prioritized genes responsible for the absorption, distribution, metabolism and excretion (ADME) of many therapeutic agents. This consensus list of genes and variants was based on the ADME core and extended gene lists compiled by a group of pharmaceutical companies as having relevance. Although these pharmacokinetic genes and pathways are well known, tools that can interrogate a large number of these genes simultaneously within a single experiment are not currently available. METHODS: Using novel design strategies, we have developed an optimized and validated ADME genotyping panel, encompassing approximately 3000 variants, that has broad applicability to any study or clinical trial that would benefit from the evaluation of an extensive list of ADME genes. RESULTS & CONCLUSION: Over the course of three design iterations, overall assay conversion rates were improved from 83 to 97% resulting in a panel that fills in many of the gaps in coverage present on currently available commercial genotyping assays. The utility of the assay has been demonstrated by the screening of more than 1000 samples resulting in the discovery of novel pharmacogenomic associations. The assay, and the underlying methods, will continue to be a valuable tool for use in future pharmacogenomic studies.
