Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis.

Abstract

We examined the causal direction between gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) or its predecessors and cardiometabolic diseases, such as risk of type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), myocardial infarction (MI), stroke, atrial fibrillation (AF), and chronic kidney disease (CKD). We used genetic variants as instruments to test the causal associations. Genetically predicted higher TMAO and carnitine were not associated with higher odds of T2DM, AF, CAD, MI, stroke, and CKD after Bonferroni correction (P ≤ 0.0005). However, we observed that genetically increased choline showed a suggestive association with higher risk of T2DM (odds ratio 1.84 [95% CI 1.00-3.42] per 10 units, P = 0.05). In contrast, genetically predicted higher betaine (0.68 [0.48-0.95] per 10 units, P = 0.023) was suggestively associated with a lower risk of T2DM. We observed a suggestive association of genetically increased choline with a lower level of body fat percentage (β ± SE -0.28 ± 0.11, P = 0.013) but a higher estimated glomerular filtration rate (0.10 ± 0.05, P = 0.034). We further found that T2DM (0.130 ± 0.036, P < 0.0001) and CKD (0.483 ± 0.168, P = 0.004) were causally associated with higher TMAO levels. Our Mendelian randomization findings support that T2DM and kidney disease increase TMAO levels and that observational evidence for cardiovascular diseases may be due to confounding or reverse causality.

• Authors: Jinzhu Jia, Pan Dou, Meng Gao, Xuejun Kong, Changwei Li, Zhonghua Liu, Tao Huang
• Journal: Diabetes (Diabetes) Vol. 68 Issue 9 Pg. 1747-1755 (09 2019) ISSN: 1939-327X [Electronic] United States
• PMID: 31167879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by the American Diabetes Association.

Chemical References

• Biomarkers

Topics

• Adiposity (physiology)
• Biomarkers
• Body Mass Index
• Cardiovascular Diseases (genetics, metabolism)
• Gastrointestinal Microbiome
• Genome-Wide Association Study
• Humans
• Mendelian Randomization Analysis
• Metabolic Diseases (genetics, metabolism)