Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach.
PLoS Med
; 14(1): e1002215, 2017 Jan.
Article
em En
| MEDLINE
| ID: mdl-28095459
ABSTRACT
BACKGROUND:
The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS ANDFINDINGS:
We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination.CONCLUSIONS:
We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença da Artéria Coronariana
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Índice de Massa Corporal
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Regulação da Expressão Gênica
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Metilação de DNA
/
Metabolismo dos Lipídeos
/
Leucócitos
Tipo de estudo:
Clinical_trials
/
Etiology_studies
/
Prognostic_studies
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Risk_factors_studies
Limite:
Aged
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
PLoS Med
Assunto da revista:
MEDICINA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos