Abstract MP18: DNA Methylation Variants, B Vitamins Intake, and Long-Term Weight Change: Gene-Diet Interactions in Two Us Cohorts

Background: The first epigenome-wide association study of body-mass index (BMI) identified DNA methylation at a HIF3A locus associated with BMI. However, the DNA methylation-associated genetic variants themselves were not associated with BMI. We aimed to test the hypothesis that DNA methylation variants might be associated with BMI according to intake of B vitamins, established metabolic cofactors of methylation. Methods: We analyzed the interaction between DNA methylation-associated HIF3A variants (rs3826795 and rs8102595) and intake of B vitamins in relation to BMI and its 10-year change in 8109 women from the Nurses’ Health Study (NHS) and 6761 men from the Health Professionals Follow-up Study (HPFS). Intake of B vitamins was assessed by validated semi-quantitative food frequency questionnaires. Results for the two cohorts were pooled by means of inverse-variance-weighted, fixed-effects meta-analyses. Results: In meta-analyses of the NHS and HPFS, DNA methylation variants were not associated with adiposity measures. However, we found significant interactions between the DNA methylation-associated HIF3A SNP rs3826795 and habitual intake of B vitamins in relation to 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B2 and vitamin B12 intake in the NHS and HPFS. In combined analyses of cohorts, the differences in the continuous BMI changes per increment of minor allele (A allele) were -0•10 (SE 0•06), -0•01 (SE 0•06), and 0•12 (SE 0•07) kg/m2 within subgroups defined by increasing tertiles of total vitamin B2 intake (all P for interaction Conclusions: In the combined data from these two cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with intakes of vitamin B2, vitamin B12, and folate. These findings, which should be replicated, suggest a potential causal relation between DNA methylation and adiposity.