Oxylipins signature to monitor the cardiometabolic status and its response to dietary intervention
Background and aim
There is an urgent need to find reliable early biomarkers of the cardiometabolic syndrome (CardMetS) allowing intervention before irreversible damage develops while assessing the efficacy of nutritional prevention. Oxylipins could be relevant candidate biomarkers thanks to their involvement in the homeostatic regulation of various process related to the cardiometabolic status and the consistent link reported between diet, oxylipins and cardiometabolic dysregulations. Moreover, the oxylipin profiling could provide a mechanistic signature at the metabolite level allowing a better stratification of patients at risk of cardiometabolic diseases (CVD and diabetes).
Our main objective in the OXYGENATE project was to uncover and validate the oxylipin signatures reflecting the cardiometabolic status or its early transition towards the CardMetS. To achieve this goal, we proposed a multidisciplinary project involving experts in lipidomics, nutrition and epidemiology and combining the comprehensive and quantitative lipidomic profiling of circulating oxylipins and the use of different biobanks from large prospective cohorts and different whole-diet interventions.
The OXYGENATE project started with the optimization of the MS-based targeted lipidomic profiling of oxylipins. The optimized method developed allows a comprehensive profiling of all types of oxylipins including the free and the esterified forms. The method has been validated through a round robin test involving 5 different laboratories worldwide and allowing to determine for each oxylipin (i) intra- and inter-day variabilities and (ii) consensus values and their respective dispersion. The OXYGENATE consortium also provided a detailed SOP for sample storage and preparation including quantitative and qualitative data regarding oxylipin stability. Using this original method, we have generated the oxylipin profiles of over 1000 participants involved in various independent studies (cross-sectional and longitudinal observational studies and intervention studies) performed in four different populations (Polish, French, Danish and American). So far, the cross-sectional studies nested in the Polish branch of the PURE cohort and the French Nutrinet-Santé cohort lead to the identification of a signature of 23 oxylipins coined OxyScore. This score is highly discriminant of CardMetS and has high performances of classification and replicability. Moreover, the identified oxylipins provide a unique mechanistic signature of MetS that may enhance the prediction of cardiometabolic diseases risk. Complementary cross-sectional studies nested in the same cohorts have been performed to investigate the links between the OxyScore and diet. Moreover, to further validate the OxyScore, we have tested its ability to monitor the changes of cardiometabolic health in response to diet using the biocollection collected in two independent studies (the Danish SHOPUS study and the American iMAPS study).
On completion, the OXYGENATE project has (i) provided an internationally validated method of comprehensive oxylipins profiling (ii) generated the 1st large diet- and health-related oxylipins database, (iii) identified and validated the oxylipins reflecting the cardiometabolic status and the quality of dietary patterns (biostatistics under progress) (iv) provided a proof-of-concept of the ability of oxylipins to monitor the effect of diet on the cardiometabolic status (biostatistics under progress). It is expected that the oxylipins identified and validated will allow a better detection and management of the cardiometabolic diseases.
|Centre de Recherche en Épidémiologies
|University of Copenhagen
|University of Wuppertal
|Wroclaw Medical University
In the framework of the JPI-Oxygenate project we have:
- Standardized and validated a MS-based method for the quantitative analysis of over 130 oxylipins including all species found in the free form and esterified into complex circulating lipids.
- Showed that total plasma oxylipins (sum of free and esterified) are stable regarding delays during plasma generation and long-term storage at −80°C.
- Showed that our MS-based method for the quantitative analysis of total oxylipins in plasma has a low technical variability and allow reliable, reproducible and comparable oxylipin concentrations in independent laboratories.
- Identified an oxylipin signature of cardiometabolic syndrome having high performances of classification and replicability.
- Showed that the oxylipin signature of cardiometabolic syndrome provides a unique mechanistic phenotyping informing on crucial molecular pathways that may help identify patients at high risk of cardiometabolic diseases.
Author: Cécile Gladine*, Annika I. Ostermann*, John W. Newman*, Nils Helge Schebb*
Author: Elisabeth Koch*, Malwina Mainka*, Céline Dalle*, Annika I. Ostermann*, Katharina M. Rund*, Laura Kutzner*, Laura-Fabienne Froehlich*, Justine Bertrand-Michel*, Cécile Gladine*, Nils Helge Schebb*
Author: Harmonized procedures lead to comparable quantification of total oxylipins across laboratories
Author: Cécile Gladine* and Maria Fedorova
At this stage, we have two main conclusions. The first one is related to the analytical aspects of the project that are of upmost importance in the field of biomarker discovery and validation. We have showed that although challenging, the quantitative analysis of oxylipins can be achieved with low technical variability, high reliability and comparability provided that a standardized and harmonized operative procedure is followed. The second main conclusion is related to the phenotyping of cardiometabolic syndrome that need to go deeper in the molecular pathways. The comprehensive profiling of oxylipins allows such a mechanistic phenotyping and could help clinicians to better understand, stratify and ultimately prevent the risk of cardiometabolic diseases. We are currently in the process of completing the analysis of the links between oxylipins and diet that should bring new conclusions concerning the potential of oxylipins as mediators of the effects of diet on cardiometabolic health. This will answer one of the main objective of the JPI-HDHL that is to understand the relationship between diet and health.
Based on these two main conclusions, a first follow-up research will be to extend the interlaboratory comparison of our MS-based oxylipin profiling method to other labs of the lipidomics community in order to promote the harmonization of oxylipin profiling and to generate high quality open-access databases for future health-related association studies. Concerning the identified oxylipin signature, although we provided first evidence of its replicability, we recommend further validation in various and larger-scale population studies to confirm and extend our findings. It will notably be important to conduct stratified analysis that were not possible in our studies and that could reveal important factors such as ageing influencing the oxylipin signature and the risk of cardiometabolic diseases. Such large population studies are also mandatory for the clinical qualification of the oxylipin signature. Finally, although this was not an initial objective of the JPI-Oxygenate project, we observed high interindividual variability in the oxylipin profiles of the selected participants of our studies. Specifically investigating these aspects of population heterogeneity could help to better understand the variability of responses to dietary intervention (notably with omega 3 fatty acids) and pave the way to future personalized nutrition strategy.