Lipid metabolic networks, Mediterranean diet and cardiovascular disease in the PREDIMED trial

BACKGROUND: Perturbed lipid metabolic pathways may play important roles in the development of cardiovascular disease (CVD). However, existing epidemiological studies have focused more on discovering individual lipid metabolites for CVD risk prediction rather than assessing metabolic pathways. METHODS: This study included a subcohort of 787 participants and all 230 incident CVD cases from the PREDIMED trial. Applying a network-based analytical method, we identified lipid subnetworks and clusters from a global network of 200 lipid metabolites and linked these subnetworks/clusters to CVD risk. RESULTS: Lipid metabolites with more double bonds clustered within one subnetwork, whereas lipid metabolites with fewer double bonds clustered within other subnetworks. We identified 10 lipid clusters that were divergently associated with CVD risk. The hazard ratios [HRs, 95% confidence interval (CI)] of CVD per a 1-standard deviation (SD) increment in cluster score were 1.39 (1.17-1.66) for the hydroxylated phosphatidylcholine (HPC) cluster and 1.24 (1.11-1.37) for a cluster that included diglycerides and a monoglyceride with stearic acyl chain. Every 1-SD increase in the score of cluster that included highly unsaturated phospholipids and cholesterol esters was associated with an HR for CVD of 0.81 (95% CI, 0.67-0.98). Despite a suggestion that MedDiet modified the association between a subnetwork that included most lipids with a high degree of unsaturation and CVD, changes in lipid subnetworks/clusters during the first-year follow-up were not significantly different between intervention groups. CONCLUSIONS: The degree of unsaturation was a major determinant of the architecture of lipid metabolic network. Lipid clusters that strongly predicted CVD risk, such as the HPC cluster, warrant further functional investigations. This work was supported by a research grant from the National Institutes of Health [R01 HL118264]. The Prevención con Dieta Mediterránea (PREDIMED) trial was supported by the official funding agency for biomedical research of the Spanish government, the Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial (RTIC G03/140 to R.E. and RTIC RD 06/0045 to Dr. Miguel A. Martínez-González) and through the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición and by grants from: the Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007); the Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505 and PI13/00462); the Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03); the Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007); the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042); and the Regional Government of Navarra (P27/2011). Dr. Dong D Wang was supported by a postdoctoral fellowship granted by the American Heart Association (16POST31100031)