Trimethylamine-N-oxide (TMAO) determined by LC-MS/MS: distribution and correlates in the population-based PopGen cohort

Background: Accumulating evidence indicates that -trimethylamine-N- oxide (TMAO) may play a causal role in cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes (T2D). TMAO plasma concentrations show considerable intra- and inter-individual variation, underscoring the need for a reference interval in the general population to identify elevated TMAO concentrations. Methods: TMAO concentrations were determined using an LC-MS/MS assay in a community-based sample of the PopGen control cohort consisting of 694 participants (54% men; aged 25-82 years) free of clinical CVD, CKD and T2D. We defined reference intervals for TMAO concentrations in human plasma using the 2.5th and 97.5th percentiles. Using multivariable regression analysis we analyzed the association of estimated glomerular filtration rate (eGFR), sex, and dietary intake and TMAO plasma concentrations. Results: TMAO plasma concentrations were positively skewed and differed by sex. The median TMAO plasma concentration in men was 3.91 (Q1-Q3: 2.87-6.10) mu mol/L and the reference interval 1.28-19.67 mu mol/L (2.5th-97.5th percentile). In women median TMAO plasma concentration was 3.56 (Q1-Q3: 2.41-5.15) mu mol/L and the reference interval 1.08-17.12 mu mol/L. In multivariable regression analysis plasma TMAO was associated with sex, renal function and diet. The association of TMAO and diet was significant for intake of fish and shellfish in men only. Conclusions: In a community-based sample free of apparent CVD and renal disease, we report the distribution of TMAO plasma concentrations with sex, renal function and diet as factors associated with plasma TMAO, and suggest reference intervals. These data may facilitate standardized comparisons of TMAO across populations.