Divergence between circulating trimethylamine and trimethylamine-N-oxide associated with common flavin-containing monooxygenase 3 variation.

Flavin-containing monooxygenase 3 (FMO3) oxidizes trimethylamine (TMA), a gut-derived metabolite of dietary substrates such as choline and betaine, into trimethylamine-N-oxide (TMAO), which has been linked to cardiometabolic and renal diseases. We examined whether two common FMO3 genetic variants, p.Glu158Lys (E158K, rs2266782) and p.Glu308Gly (E308G, rs2266780), were associated with circulating TMA and TMAO in a sub-study of a randomized clinical trial incorporating dietary substrate loads (136 fasting samples from four visits). Each Gly308 allele was associated with approximately 18% lower plasma TMAO concentrations and accounted for approximately one-third of baseline ln(TMAO) variation, independent of rs2266782 and robust to adjustment for estimated glomerular filtrate rate. In contrast, plasma TMA concentrations did not differ by genotype. No consistent genotype effects were observed for blood pressure, although systolic blood pressure showed a genotype × treatment interaction without main genotype or treatment effects. Given the small sample size and sparse genotype representation, these findings should be interpreted as exploratory and may reflect variation in TMA oxidation efficiency. In conclusion, this initial study suggests that individuals carrying the Gly308 variant exhibit lower circulating TMAO without detectable increases in TMA, consistent with preserved short-term substrate handling under controlled conditions and motivating further investigation of the TMA-TMAO pathway in larger, genotype-balanced cohorts.