Dihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology

Abstract

Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n = 775]; cardiovascular disease [CVD, n = 551]; random subcohort [n = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides C20:0 and C22:2 are associated with higher and ceramide C20:0 and dihydroceramide C26:1 with lower T2D risk. Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Genome-wide association studies and Mendelian randomization analyses support a role of ceramide C22:0 in T2D etiology. Our results also suggest that (dh)ceramides partly mediate the putative adverse effect of high red meat consumption and benefits of coffee consumption on T2D risk. Thus, (dihydro)ceramides may play a critical role in linking genetic predisposition and dietary habits to cardiometabolic disease risk.

Fig. 1. Distribution of ceramide and dihydroceramide measurements.

A Distribution of the absolute (dh)ceramide plasma concentrations; note that the x-axis is log scaled. B Comparison of Z-scores derived from the non-transformed and log-transformed (dh)-ceramide plasma concentrations. Cer ceramide, dhCer dihydroceramide.

Fig. 2. Data-driven conditional independence network of (dh)ceramides.

Bars within nodes show network-adjusted cardiometabolic disease risk. Left: T2D risk; Right: CVD risk; Orange: increased risk; Blue: decreased risk; Numbers: percent risk change with 1 standard deviation higher (dh)ceramide concentration. Frame colors—Green: only T2D-associated; Purple: only CVD-associated; Brown: T2D- and CVD-associated. CER ceramide, dhCER dihydroceramide.

Fig. 3. Mediation analysis.

A Adjusted effect estimates (beta coefficients) of red meat on T2D-related (dh)ceramides (direction of associations consistent with mediation hypothesis; p-values < 0.05, one-sided t-test). B Attenuation of the putative effect of red meat on T2D risk after adjustment for red meat- and T2D-related (dh)ceramides. C Adjusted effect estimate (beta coefficient) of coffee on T2D-related dhCer22:2 (direction of the association consistent with the mediation hypothesis; p-value < 0.05, one-sided t-test). D Attenuation of the putative effect of coffee on T2D risk after adjustment for coffee- and T2D-related dhCer22:2. All models were extensively adjusted for potential confounders (age, sex, fasting status, total energy intake, leisure-time physical activity, medication, smoking, alcohol consumption, and education). Blue indicates inverse association (i.e., lower ceramide concentration or T2D risk), orange: positive association (i.e., higher ceramide concentration or T2D risk). Total effect is the confounder-adjusted hazard ratio (95% CI) per exposure unit: red meat, 2 SD (~1 portion per day); coffee, two cups (300 mL) per day. PE Proportion explainable, i.e., relative attenuation of the total effect through mediator-adjustment. Cer ceramide, dhCer dihydroceramide.