Broadcasters, receivers, functional groups of metabolites, and the link to heart failure by revealing metabolomic network connectivity
Journal article, 2024
Background and Objective: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline.
Methods: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. We incorporated the network structure into the identification of metabolites associated with HF to control the effect of confounding metabolites.
Results: We identified metabolites associated with higher and lower risk of HF incidence, such as glycine, ureidopropionic and glycocholic acids, and LPC 18:2. These associations were not confounded by the other metabolites due to uncovering the connectivity among metabolites and adjusting each association for the confounding metabolites. Examples of our findings include the direct influence of asparagine on glycine, both of which were inversely associated with HF. These two metabolites were influenced by polygenic factors and only essential amino acids, which are not synthesized in the human body and are obtained directly from the diet.
Conclusion: Metabolites may play a critical role in linking genetic background and lifestyle factors to HF incidence. Revealing the underlying connectivity of metabolites associated with HF strengthens the findings and facilitates studying complex conditions like HF.
Methods: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. We incorporated the network structure into the identification of metabolites associated with HF to control the effect of confounding metabolites.
Results: We identified metabolites associated with higher and lower risk of HF incidence, such as glycine, ureidopropionic and glycocholic acids, and LPC 18:2. These associations were not confounded by the other metabolites due to uncovering the connectivity among metabolites and adjusting each association for the confounding metabolites. Examples of our findings include the direct influence of asparagine on glycine, both of which were inversely associated with HF. These two metabolites were influenced by polygenic factors and only essential amino acids, which are not synthesized in the human body and are obtained directly from the diet.
Conclusion: Metabolites may play a critical role in linking genetic background and lifestyle factors to HF incidence. Revealing the underlying connectivity of metabolites associated with HF strengthens the findings and facilitates studying complex conditions like HF.
Genetic variation
Heart failure
Metabolomics
Structural equation modeling
Causal networks
Confounding metabolites
Data-driven or Bayesian networks
Author
Azam Yazdani
Broad Institute
Harvard Medical School
Raul Mendez-Giraldez
Beckman Coulter
Akram Yazdani
University of Texas Medical School
Rui Sheng Wang
Harvard Medical School
Daniel J. Schaid
Mayo Clinic
Sek Won Kong
Children's Hospital Boston
M. Reza Hadi
Iran University of Science and Technology
Ahmad Samiei
Children's Hospital Boston
Esmat Samiei
Gamelectronic
Clemens Wittenbecher
Chalmers, Life Sciences, Food and Nutrition Science
Jessica Lasky-Su
Harvard Medical School
Clary B. Clish
Broad Institute
Jochen D. Muehlschlegel
Harvard Medical School
Francesco Marotta
ReGenera R & amp;D International for Aging Intervention and Vitality & amp; Longevity Medical Science Commission
Joseph Loscalzo
Harvard Medical School
Samia Mora
Harvard Medical School
Daniel I. Chasman
Harvard Medical School
Martin G. Larson
Boston University
Sarah H. Elsea
Baylor College of Medicine
Metabolomics
1573-3882 (ISSN) 1573-3890 (eISSN)
Vol. 20 4 71Subject Categories
Cardiac and Cardiovascular Systems
Nutrition and Dietetics
DOI
10.1007/s11306-024-02141-y