GWAS of Folate Metabolism With Gene–environment Interaction Analysis Revealed the Possible Role of Lifestyles in the Control of Blood Folate Metabolites in Japanese: The J-MICC Study

Abstract

Background: The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene–environment interactions in Japanese.

Methods: We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B₁₂ (VB₁₂) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene–environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed.

Results: For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10⁻⁸). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB₁₂. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and −0.054, P = 0.018, 0.021 and <0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (β = 0.033, P = 0.048).

Conclusion: The present GWAS revealed the folate metabolism-associated genetic loci and gene–environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized cardiovascular disease prevention.