Unraveling interindividual variation of trimethylamine N‐oxide and its precursors at the population level

Author:

Andreu‐Sánchez Sergio12ORCID,Ahmad Shahzad34ORCID,Kurilshikov Alexander1ORCID,Beekman Marian5ORCID,Ghanbari Mohsen3ORCID,van Faassen Martijn6,van den Munckhof Inge C. L.7,Steur Marinka3,Harms Amy4,Hankemeier Thomas4,Ikram M. Arfan3ORCID,Kavousi Maryam3ORCID,Voortman Trudy3ORCID,Kraaij Robert8ORCID,Netea Mihai G.7ORCID,Rutten Joost H. W.7,Riksen Niels P.7ORCID,Zhernakova Alexandra1ORCID,Kuipers Folkert269ORCID,Slagboom P. Eline5ORCID,van Duijn Cornelia M.10,Fu Jingyuan12ORCID,Vojinovic Dina35ORCID

Affiliation:

1. Department of Genetics, University Medical Center Groningen University of Groningen Groningen The Netherlands

2. Department of Pediatrics, University Medical Center Groningen University of Groningen Groningen The Netherlands

3. Department of Epidemiology Erasmus University Medical Center Rotterdam The Netherlands

4. Metabolomics & Analytics Centre, Leiden Academic Center for Drug Research Leiden University Leiden The Netherlands

5. Molecular Epidemiology, Department of Biomedical Data Sciences Leiden University Medical Center Leiden The Netherlands

6. Department of Laboratory Medicine, University Medical Center Groningen University of Groningen Groningen The Netherland

7. Department of Internal Medicine and Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen The Netherlands

8. Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands

9. European Institute for the Biology of Ageing, University Medical Center Groningen University of Groningen Groningen The Netherlands

10. Nuffield Department of Population Health University of Oxford Oxford UK

Abstract

AbstractTrimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO‐to‐precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish‐TMAO, meat‐carnitine, and plant‐based food‐betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Publisher

Wiley

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