Background: In blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification. Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam cohort study comprises 27,548 participants recruited within an age-range of 35-65 years from the general population around Potsdam, Germany. We generated two disease-specific case-cohorts based on a fixed random subsample (n=1,262) and all respective cohort-wide identified incident primary cardiovascular disease (CVD, composite of fatal and non-fatal myocardial infarction and stroke) (n=551) and type 2 diabetes (T2D) (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in The Dietary Intervention and VAScular function randomized controlled trial (DIVAS) (n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks. Results: 69 lipids associated (false discovery rate (FDR) <0.05) with at least one outcome (both=8, only CVD=49, only T2D=12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes, cholesteryl esters, free fatty acids, and sphingolipids were largely CVD-specific, and several (glycero)phospholipids T2D-specific. In addition, nineteen risk-associated lipids were affected (FDR<0.05) by the diets rich in unsaturated dietary FAs compared to the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased DG(FA16:0) by 0.4 (95%-CI:0.5,0.3) SD-units and increased TG(FA22:1) by 0.5 (95%-CI:0.4,0.7) SD-units. Conclusions: We identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention, which supports substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention.

Background: Plasma odd-chain saturated fatty acids (OCFA) are inversely associated with type 2 diabetes (T2D) risk and may serve as biomarkers for dairy fat intake. Their distribution across different lipid classes and consequences for diabetes risk remain unknown. Aim: To investigate the prospective associations of OCFA-containing lipid species with T2D risk and their dietary determinants. Methods: Within the European Prospective Investigation into Cancer and NutritionePotsdam study (n ¼ 27,548), we applied a nested case-cohort design (subcohort: n ¼ 1248; T2D cases: n ¼ 820; median follow-up 6.5 years). OCFA-containing lipids included triacylglycerols, free fatty acids (FFA), cholesteryl esters (CE), phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, monoacylglycerols, and diacylglycerols. We estimated lipid class-specific associations between OCFA-containing lipids and T2D in sex-stratified Cox proportional-hazards models. We investigated correlations between lipids and dietary intakes derived from food-frequency questionnaires. Results: We observed heterogeneous integration of OCFA in different lipid classes: triacylglycerols, FFA, CE, and phosphatidylcholines contributed most to the total OCFA-plasma abundance. The relative concentration of OCFA was particularly high in monoacylglycerols, and the contribution of C15:0 versus C17:0 to the total OCFA-abundance differed across lipid classes. In women, several OCFA-containing phospholipids were inversely associated with T2D risk [phosphatidylcholine(C15:0), HR Q5 vs Q1: 0.56, 95% CI 0.32e0.97; phosphatidylcholine(C17:0), HR per SD: 0.59, 95% CI 0.48e0.71; lysophosphatidylcholine(C17:0), HR Q5 vs Q1: 0.42, 95% CI 0.23e0.76]. In men, we did not detect statistically significant inverse associations in phospholipids, and lysophosphatidylcholine(C15:0) was associated with higher T2D risk (HR Q1 vs. Q5: 1.96, 95% CI 1.06e3.63). Besides, CE(C17:0), monoacylglycerols(C15:0), and diacylglycerols(C15:0) were inversely associated with T2D risk; FFA(C17:0) was positively associated with T2D risk in women. Consumption of fat-rich dairy and fiber-rich foods were positively and red meat inversely correlated to OCFA-containing lipid plasma levels. Conclusions: OCFA-containing lipids are linked to T2D risk in a lipid class and sex-specific manner, and they are correlated with several foods.