Trimethylamine N-oxide and its precursors in relation to blood pressure: A mendelian randomization study

Abstract

ObjectivePrevious studies have demonstrated that trimethylamine N-oxide (TMAO) and its precursors, including choline, betaine, and carnitine, are closely associated with blood pressure (BP) changes. Nevertheless, with the limitation of reverse causality and confounder in observational studies, such a relationship remains unclear. We aimed to assess the causal relationship of TMAO and its precursors with BP by the Mendelian Randomization (MR) approach.MethodIn this study, two-sample MR was used to reveal the causal effect of TMAO and its precursors on BP. Pooled data of TMAO and its precursors was from genome-wide association studies (GWAS) which includes summary data of human metabolome in 2,076 European participants from Framingham Heart Study. Summary-level data for BP was extracted from the International Consortium of Blood Pressure-Genome Wide Association Studies. Inverse variance weighted (IVW), MR Egger regression, Maximum likelihood, Weighted median, and MR pleiotropy residual sum and outlier test (MR-PRESSO) were used in this MR analysis.ResultsA total of 160 independent SNP loci were associated with TMAO and three precursors, including 58 associated with TMAO, 29 associated with choline, 44 associated with betaine, and 29 associated with carnitine, were selected. MR results suggested that a 1 unit increase in TMAO should be associated with a 1SD increase in systolic BP mmHg (beta: 0.039, SE, 0.072, p = 0.020). Additionally, our findings also indicated that a 1 unit increase in carnitine should be associated with a 1SD increase in systolic BP mmHg (beta: 0.055, SE: 0.075, p = 0.039). This result was also confirmed by sensitivity analysis methods such as Maximum likelihood, MR-PRESSO, and Weighted median. No effects of betaine or choline on systolic or diastolic BP were observed in the present study.ConclusionOur study provides evidence of a causal relationship of TMAO and its precursors with BP, suggesting that mediating the generation of TMAO would be beneficial for lowering BP.

Increased plasma trimethylamine-N-oxide levels are associated with mild cognitive impairment in high cardiovascular risk elderly population

“…The Mendelian Randomization approach showed that an increase in TMAO 1 unit was associated with a 1SD increase in systolic blood pressure in mmHg. 67 TMAO-related lipid and glucose metabolism could contribute to hypertension. 59 Additionally, TMAO could aggravate angiotensin II-induced vasoconstriction, resulting in hypertension and impaired renal function.…”

Association of the gut microbiota with coronary artery disease and myocardial infarction: A Mendelian randomization study

“…In several large independent clinical cohorts, plasma TMAO levels were shown to be associated with the risk of CAD morbidity and long-term mortality and thus predictors of cardiovascular risk (Tang et al, 2013;Wang et al, 2014). However, in the MR study, there is no direct causal relationship between TMAO and CAD, but a suggestive association of genetically increased choline with a higher risk of T2DM (Jia et al, 2019) and the same effect of TMAO and carnitine with systolic BP (Wang et al, 2022). Butyrate is a short-chain fatty acid (SCFA) produced by the metabolism of intestinal microflora, which has been proved to be a protective metabolite for CAD in contrast to TAMO (Hu et al, 2022).…”

Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?

“…Only three MR studies were performed focusing on the role of TMAO. The first one assessed the association of gut-microbiota-related metabolites and cardiometabolic health [49]; the second was in relation to Alzheimer's disease [50]; and the most recent was in relation to blood pressure [51]. In the study of Jia et al, they did not find a significant association of genetically predicted higher TMAO levels with cardiometabolic disease (including T2D, atrial fibrillation, CAD, MI, stroke, and CKD).…”