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1.
Age Ageing ; 52(1)2023 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-36729470

RESUMEN

BACKGROUND: numerous studies point towards a critical role of Interleukin 6 (IL-6) pathway in frailty pathogenesis yet the causal relationship between the two remains elusive. METHODS: we selected genetic variants near the IL-6 receptor locus (IL-6R) associated with reduced C-reactive protein (CRP) levels, a downstream effector of IL-6 pathway, and we used them as genetic proxies of IL-6 signalling downregulation. We then performed a two-sample Mendelian randomisation (MR) to investigate the association with frailty status, as defined by the Frailty Index (FI) in 11,171 individuals from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD) study. MR analysis was repeated after excluding depression or cognition-related FI items as well as following age or sex stratification. Association with frailty was also examined using an alternative instrument, weighted on s-IL-6R levels. Replication was attempted in UK Biobank dataset. RESULTS: genetic predisposition to IL-6 signalling downregulation, weighted on CRP levels, was associated with lower risk of frailty, inserted either as categorical (odds ratio [95% confidence interval] = 0.15 [-3.39, -0.40], P = 0.013) or continuous variable (beta [se] = -0.09 [0.003], P = 0.0009). Sensitivity analyses revealed similar estimates across different MR methods with no evidence for horizontal pleiotropy or heterogeneity. Results remained robust after exclusion of depression or cognition-related FI items and following sex or age stratification. Genetically increased s-IL-6R levels were negatively correlated with frailty and this finding remained significant in a meta-analysis of UK Biobank and HELIAD cohorts. CONCLUSION: our results support a potential causal effect of IL-6 signalling on frailty and further suggest that downregulation of IL-6 levels may reduce frailty risk.


Asunto(s)
Fragilidad , Humanos , Fragilidad/diagnóstico , Fragilidad/genética , Interleucina-6/genética , Estudios Longitudinales , Envejecimiento/genética , Análisis de la Aleatorización Mendeliana/métodos
2.
JCI Insight ; 6(17)2021 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-34375307

RESUMEN

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.


Asunto(s)
Proteínas de Unión a Calmodulina/genética , Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/genética , Adulto , Anciano , Proteínas de Unión a Calmodulina/biosíntesis , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Metilación de ADN , ADN de Neoplasias/genética , Femenino , Perfilación de la Expresión Génica , Hepatitis B Crónica/genética , Hepatitis B Crónica/patología , Humanos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad
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