RESUMEN
The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Trastornos Relacionados con Alcohol/genética , Metilación de ADN/efectos de los fármacos , Adulto , Anciano , Consumo de Bebidas Alcohólicas/metabolismo , Trastornos Relacionados con Alcohol/metabolismo , Biomarcadores/sangre , Población Negra/genética , Islas de CpG/genética , Epigénesis Genética , Etanol/sangre , Etanol/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Población Blanca/genéticaRESUMEN
In order to study when recurrences appear following conization for dysplasia or cancer in situ of the cervix uteri, a series of 477 patients has been investigated. They all underwent conization at Sabbatsberg 1965-1970. Among the 181 cases of dysplasia two developed recurrences one respectively three years after treatment. In the series of 296 patients with cancer in situ thirteen recurrences appeared. Eight of them were detected within the first three years. The other five were spread out during the next four years. About 50% of all patients had been followed-up for five years or more (Table I). The conclusion is reached that a yearly follow-up is necessary for at least ten years. As it is impossible to take care of such an accumulating number of examinations at the Swedish departments of obstetrics and gynecology without extra personnel, the following proposal is made. During the first three years after treatment the examinations are performed at the department where the conization has been performed. After that period the follow-up is limited to vaginal smears taken once every year in connection with the general gynecologic health control.