RESUMEN
Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Asunto(s)
Epigenoma , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Gota/genética , Ácido Úrico/sangre , Sistema de Transporte de Aminoácidos y+/genética , Estudios de Cohortes , Islas de CpG , Metilación de ADN , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Gota/sangre , Humanos , MasculinoRESUMEN
Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Asunto(s)
Metilación de ADN , Insuficiencia Renal Crónica/genética , Adulto , Anciano , Islas de CpG , Femenino , Tasa de Filtración Glomerular , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Riñón/metabolismo , Riñón/fisiopatología , Pruebas de Función Renal , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted.
