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Diabetes. 2019 Jun 5. pii: db190153. doi: 10.2337/db19-0153. [Epub ahead of print]

Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: Abi-Directional Mendelian Randomisation Analysis.

Jia J1,2, Dou P3, Gao M1, Kong X4, Li C5, Liu Z6, Huang T7,8,9.

Author information

1
Department of Epidemiology & Biostatistics, School of Public Health, Peking University, 100191 China.
2
Department of Biostatistics, School of Public Health, Peking University, 100191 China.
3
Department of Clinical Nutrition, Peking University First Hospital, Beijing, 100034 China.
4
Martinos Center, Massachusetts General Hospital, Charleston, MA.
5
Department of Epidemiology and Biostatistics, University of Georgia, USA.
6
Department of Statistics and Actuarial Science, The University of Hong Kong. huangtaotao@pku.edu.cn zhhliu@hku.hk.
7
Department of Epidemiology & Biostatistics, School of Public Health, Peking University, 100191 China. huangtaotao@pku.edu.cn zhhliu@hku.hk.
8
Department of Global Health, School of Public Health, Peking University, 100191 China.
9
Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education, 100191 China.

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% confidence interval: 1.00 to 3.42 per 10 units, P=0.05). In contrast, genetically predicted higher betaine (0.68, 0.48 to 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 % (beta: -0.28, SE: 0.11, P=0.013), but a higher level of estimated glomerular filtration rate (0.10±0.05, P=0.034). We further found that T2DM (beta: 0.130, SE: 0. 0.036, P<0.0001) and CKD (0.483±0.168, P=0.004) were causally associated with higher TMAO levels. Our MR findings support that T2DM and kidney disease increase TMAO levels and observational evidence for cardiovascular diseases may be due to confounding or reverse causality.

PMID:
31167879
DOI:
10.2337/db19-0153

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