1. DNA methylation at three sites within the intron of the gene HIF3A on chromosome 19 was associated with higher BMI levels.
Evidence Rating Level: 2 (Good)
Study Rundown: DNA methylation is a reversible epigenetic modification that can drastically alter gene expression. Since the extent of DNA methylation is affected by both environmental and genetic factors, the prevailing thought is that such modifications better equip the host to respond to changing external environmental conditions. In this study, Dick et al. performed the first large-scale genome-wide analysis of the association between adult BMI and DNA methylation in blood and adipose samples. Cumulative data from over 450 individuals revealed a significant association between BMI and methylation at sites within intron 1 of HIF3A. These results suggest the perturbation of pathways involved in the hypoxia inducible transcription factor could have detrimental effects on bodyweight. The study was limited by the fact that all participants were of European descent. The cross-sectional design also precluded assignment of cause-effect associations. Nevertheless, these results are pioneering steps in understanding the link between environmental perturbations, gene expression and body weight.
The study was funded by the European Commission, National Institute for Health Research, British Heart Foundation, and Wellcome Trust.
In-Depth [retrospective cohort study]: This study analyzed blood and adipose samples from 459 individuals to assess the association between DNA methylation within the HIF3A gene and adult BMI. DNA methylation was quantified as a β value, which is a continuous variable ranging from 0, indicating no methylation, to 1, indicating full methylation. The Bonferroni correction was applied for multiple testing.
Three sites within intron 1 of HIF3A were found to be significantly associated with BMI: cg22891070, cg27146050 and cg16672562. In the discovery cohorts, every 0.1 increase in methylation β value was associated with a 3.6% (95% CI, 2.4 to 4.9) higher BMI for cg22891070, 7.8% (95% CI, 5.1 to 10.4) higher BMI for cg27146050, and 3.2% (95% CI, 2.0 to 4.4) higher BMI for cg16672562. Additionally, the methylation levels of these three sites were highly correlated with each other (R2 = 0.89-0.95). In the MuTHER (Multiple Tissue Human Expression Resource) cohort, there was an association between methylation at cg22891070 and BMI in adipose tissue (p=1.72×10-5) but not in skin (P=0.882).
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