Abstract
Background: Adiposity is a major risk factor for type 2 diabetes, dyslipidemia, and CVD, suggesting an important role for adipose tissue in development of these conditions. There is interest in epigenetic mechanisms by which genetic and environmental factors may contribute to adiposity, however studies of DNA methylation in relation to adiposity rarely focus on adipose tissue. Objective: To determine whether genome-wide DNA methylation profiles in blood and adipose tissue are associated with central fat, body fat distribution, and obesity in adulthood. Methods: Participants (aged 44-50 years) were from the New England Family Study birth cohort, born in Providence, RI . Of 400 participants assessed during 2010-2011, a representative subsample of 106 participants (68 women, 38 men) was selected for DNA methylation analyses. DNA methylation in subcutaneous adipose tissue and peripheral blood leukocytes was evaluated using the Infinium HumanMethylation450K BeadChip. Dual-energy x-ray absorptiometry scans assessed android fat mass, android:gynoid region fat ratio, and trunk:limb region fat ratio. BMI (kg/m 2 ) was directly assessed. Results: Adipose tissue DNA methylation was associated with all four measures of adiposity, after adjusting for race, sex, smoking, and accounting for multiple testing (permutation-based omnibus p-values <0.001). Associations were similar in sex-specific analyses, and upon exclusion of single nucleotide polymorphisms. Investigation of top differentially-methylated genes revealed several that are biologically relevant to adiposity development, including SOD3 , AOC3 , AQP7, TIMP4, ANGPT4, and ADAMTS4 . Blood DNA methylation was not related to adiposity. Conclusion: Adipose tissue DNA methylation was associated with directly-assessed measures of central fat and body fat distribution, as well as obesity, all of which are important determinants of cardiometabolic risk. Targeting the primary affected organ may be important for elucidating the epigenetic basis of adiposity.
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