HIF3A DNA methylation, obesity and weight gain, and breast cancer risk among Mexican American women.

OBJECTIVE In previous epigenome-wide association studies, Hypoxia inducible Factor 3 Alpha Subunit (HIF3A) DNA methylation has been reported to be associated with body mass index (BMI) and weight change. However, none of these studies have included Mexican Americans. METHODS In the current study, we assessed levels of HIF3A methylation in 927 Mexican American women identified from Mano-A-Mano, the Mexican American Cohort study. RESULTS Significantly higher methylation levels at three CpG sites (position 46801557, 46801642, and 46801699) were observed in obese women compared to non-obese women (P < 0.05). Furthermore, we found that elevated methylation levels at those three CpG sites were associated with significant weight gain (P < 0.05), defined as an increase in BMI by at least one category between the baseline and the follow-up, with a median follow-up time of 39 months. Then, using pre-diagnostic blood DNA samples, we found increased DNA methylation at CpG 46801642 to be associated with a 1.35-fold increased risk of breast cancer (Hazard Ratio (HR) = 1.35, 95% Confidence Interval (CI): 1.02, 3.01), with a median follow-up time of 127 months. Using the Cancer Genome Atlas (TCGA) data, we further found that levels of HIF3A were significantly higher-methylated and down-regulated in breast tumor than in normal tissues (P < 1 × 1012 for both). CONCLUSION Thus, our results provide evidence to support the role of HIF3A in obesity, weight gain, and the development of breast cancer.