Genetic and environmental influences on serum oxylipins, endocannabinoids, bile acids and steroids

Authors: BERMINGHAM, KATE - University College Dublin; BRENNAN, LORRAINE - University College Dublin; SEGURADO, RICARDO - University College Dublin; Gray, Ira; BARRON, REBECCA - University College Dublin; GIBNEY, EILEEN - University College Dublin; RYAN, MIRIAM - University College Dublin; GIBNEY, MICHAEL - University College Dublin; Newman, John; O'SULLIVAN, AIFRIC - University College Dublin

Submitted to: Prostaglandins Leukotrienes and Essential Fatty Acids
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/16/2021
Publication Date: 8/25/2021
Citation: Bermingham, K.M., Brennan, L., Segurado, R., Gray, I.J., Barron, R.E., Gibney, E.R., Ryan, M.F., Gibney, M.J., Newman, J.W., O'Sullivan, A.M. 2021. Genetic and environmental influences on serum oxylipins, endocannabinoids, bile acids and steroids. Prostaglandins Leukotrienes and Essential Fatty Acids. 173. Article 102338. https://doi.org/10.1016/j.plefa.2021.102338.
DOI: https://doi.org/10.1016/j.plefa.2021.102338

Interpretive Summary: The bio-activity of dietary lipids is associated with both their direct action and the action of their metabolites, i.e. compounds produced in the body by normal biochemical processes. Oxylipins, endocannabinoids, bile acids and steroids are lipid metabolites with potent bio-activities that are involved in the regulation of multiple physiological and pathological processes that play important roles in human health and disease states. Understanding the factors contributing to the biological variability in the production of these bioactive lipids may inform future efforts to understand and treat complex metabolic states and diseases. This research aims to determine the contribution of genetic and environmental influences to bio-active lipids involved in the regulation of inflammation and energy metabolism. Using a classical study design of identical and fraternal twins (n =69 twin pairs), serum oxylipins, endocannabinoids, bile acids and steroids were analysed by liquid chromatography mass-spectrometry. Univariate twin modeling estimated the contribution of genetic and environmental influences to variation in profiled fatty acids and a suite of bioactive lipids. Bioactive lipids with high heritablity included the 12-lipoxygenase products 12-hydroxy-eicosatetraenoic acid [0.70 (95% CI: 0.12,0.82)], 12-hydroxy-eicosatetraenoic acid [0.73 (95% CI: 0.30,0.83)], 14-hydroxy-docosahexaenoic acid [0.51 (95% CI: 0.07,0.71)], along with the omega-3 fatty acid-derived endocannabinoid docosahexaenoyl-ethanolamide [0.52 (95% CI: 0.15,0.72)]. For the other measured metabolites, the contribution of unique environment to variance was stronger. With increased analytical sensitivity and understanding of the function of these bioactive lipids in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends preexisting knowledge of the genetic and environmental influences on the human lipidome, highlighting genetics as a significant contributer to systems important in the regulation of blood coagulation, glucose metabolism and inflammation.

Technical Abstract: The bioactivity of lipids is associated with both their direct action and the action of their metabolic products. Oxylipins, endocannabinoids, bile acids and steroids are potent lipid mediators involved in multiple physiological and pathological processes. These bioactive lipids play important roles in human health and disease states. Understanding the factors contributing to their biological variability may inform future approaches for the understanding and treatment of complex metabolic states and diseases. This research aims to determine the contribution of genetic and environmental influences to lipid mediators involved in the regulation of inflammation and energy metabolism. In a classical twin design, serum oxylipins, endocannabinoids, bile acids and steroids were analysed by liquid chromatography mass-spectrometry in 138 twins. Univariate twin modeling estimated the contribution of genetic and environmental influences to variation in profiled fatty acids and lipid mediators. Heritable lipid mediators included the 12-lipoxygenase products 12-hydroxy-eicosatetraenoic acid [0.70 (95% CI: 0.12,0.82)], 12-hydroxy-eicosatetraenoic acid [0.73 (95% CI: 0.30,0.83)], 14-hydroxy-docosahexaenoic acid [0.51 (95% CI: 0.07,0.71)], along with docosahexaenoyl-ethanolamide [0.52 (95% CI: 0.15,0.72)]. For others, the contribution of unique environment to variance was stronger. With increased analytical sensitivity and understanding of lipid mediator functions in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends preexisting knowledge of the genetic and environmental influences on the human lipidome.