RESUMEN
International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.
Asunto(s)
Carcinoma de Células Renales , Exposición a Riesgos Ambientales , Geografía , Neoplasias Renales , Mutágenos , Mutación , Femenino , Humanos , Masculino , Ácidos Aristolóquicos/efectos adversos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/inducido químicamente , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Genoma Humano/genética , Genómica , Hipertensión/epidemiología , Incidencia , Japón/epidemiología , Neoplasias Renales/genética , Neoplasias Renales/epidemiología , Neoplasias Renales/inducido químicamente , Mutágenos/efectos adversos , Obesidad/epidemiología , Factores de Riesgo , Rumanía/epidemiología , Serbia/epidemiología , Tailandia/epidemiología , Fumar Tabaco/efectos adversos , Fumar Tabaco/genéticaRESUMEN
The Pharmacogene Variation Consortium (PharmVar) serves as a global repository providing star (*) allele nomenclature for the polymorphic human CYP4F2 gene. CYP4F2 genetic variation impacts the metabolism of vitamin K, which is associated with warfarin dose requirements, and the metabolism of drugs, such as imatinib or fingolimod, and certain endogenous compounds including vitamin E and eicosanoids. This GeneFocus provides a comprehensive overview and summary of CYP4F2 genetic variation including the characterization of 14 novel star alleles, CYP4F2*4 through *17. A description of how haplotype information cataloged by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) is also provided.
RESUMEN
Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.
No Brasil, o uso off label de azitromicina, hidroxicloroquina e ivermectina (o "kit-COVID") foi sugerido para tratar COVID-19 sem que tivéssemos evidências clínicas ou científicas de sua eficácia. Estas drogas têm causado reações adversas (RA) em quem as tomam. Este estudo almejou analisar se a venda dos medicamentos que compõem o "kit-COVID" correlaciona-se com o número relatado de RAs após o início da pandemia da COVID-19. Os dados sobre vendas e RA associados a azitromicina, hidroxicloroquina e ivermectina foram obtidos no site da Agência Nacional de Vigilância Sanitária (Anvisa) para todos os estados brasileiros. Comparamos o período entre março de 2019 e fevereiro de 2020 (antes da pandemia) ao de março de 2020 a fevereiro de 2021 (durante a pandemia). Ajustamos tendências para os dados de séries temporais e as análises de correlação cruzada para investigar a correlação entre vendas e RA em um mesmo mês (lag 0) e nos seguintes (lag 1 e 2). O coeficiente de correlação de Spearman foi utilizado para avaliar a magnitude das correlações. Após o início da pandemia, as vendas de todos os medicamentos investigados aumentaram significativamente (69,75% para azitromicina, 10.856.481,39% para hidroxicloroquina e 12.291.129,32% para ivermectina). Os níveis de RAs de todos os medicamentos (com exceção de azitromicina) eram zero antes da pandemia mas aumentaram após seu início. A análise de correlação cruzada foi significativa no lag 1 para todas as drogas em todo o país. A correlação de Spearman foi moderada para azitromicina e hidroxicloroquina, mas ausente para ivermectina. Os dados devem ser interpretados com cautela, uma vez que não realizamos uma busca ativa por RA. Nossos resultados mostram que o uso aumentado e indiscriminado do "kit-COVID" durante a pandemia se correlaciona com uma ocorrência aumentada de RAs.
Se ha sugerido el uso fuera de lo establecido de azitromicina, hidroxicloroquina e ivermectina (el "kit-COVID") para el tratamiento de la COVID-19 en Brasil sin evidencia clínica o científica de su eficacia. Estos medicamentos tienen reacciones adversas (RAM) conocidas. Este estudio pretendía analizar si las ventas de medicamentos del "kit-COVID" están correlacionadas con el número de reacciones adversas notificadas tras el inicio de la pandemia de COVID-19. Los datos se obtuvieron del sitio web de la Agencia Nacional de Vigilancia Sanitaria (Anvisa) sobre las ventas y las RAM notificadas para la azitromicina, la hidroxicloroquina y la ivermectina para todos los estados brasileños. Se comparó el periodo de marzo de 2019 a febrero de 2020 (antes de la pandemia) con el de marzo de 2020 a febrero de 2021 (durante la pandemia). Se realizó un ajuste de tendencia para los datos de las series de tiempo y un análisis de correlación cruzada para investigar la correlación entre las ventas y la RAM dentro del mismo mes (lag 0) y en los meses siguientes (lag 1 y lag 2). Se utilizó el coeficiente de correlación de Spearman para evaluar la magnitud de las correlaciones. Tras el inicio de la pandemia, las ventas de todos los medicamentos investigados aumentaron significativamente (69,75% para la azitromicina, 10.856.481,39% para la hidroxicloroquina y 12.291.129,32% para la ivermectina). Los niveles de RAM de todos los medicamentos, excepto la azitromicina, eran nulos antes de la pandemia, pero aumentaron tras su inicio. El análisis de correlación cruzada fue significativo en el lag 1 para todos los medicamentos a nivel nacional. La correlación de Spearman fue moderada para la azitromicina y la hidroxicloroquina, pero no para la ivermectina. Los datos deben interpretarse con cautela, ya que no se realizó una búsqueda activa de RAM. Nuestros resultados muestran que el uso creciente e indiscriminado del "kit-COVID" durante la pandemia se correlaciona con una mayor aparición de las RAM.