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

C Wittenbecher,M Prada,F Eichelmann,P Hoffman,S Jäger,F B Hu,L Johnston,F Del Greco M,A A Hicks,J Krumsiek,M B Schulze,R Cuadrat,O Kuxhaus

doi:10.1038/s41467-022-28496-1

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.

Highlights

The observational analyses were based on the measurement of ceramides andceramides from a large lipidomics dataset in two case-cohort samples nested within the prospective EPIC-Potsdam study (775 participants with incident Type 2 diabetes (T2D) among 1886 at-risk participants, and 551 participants with incident cardiovascular disease (CVD) among 1671 at-risk participants)
In the random subcohort (n = 1137; baseline-prevalent T2D cases excluded), representative for the full EPIC-Potsdam cohort at cardiometabolic risk, the median plasma concentrations ranged between 0.2 nM (Cer18:1) and 42 nM (Cer24:0) for ceramides, and 0.62 nM and 11 nM for dihydroceramides
When simultaneously included in a confounder- and total ceramide and dihydroceramide-adjusted Cox model, high plasma concentrations of Cer18:0, Cer22:0, dhCer20:0, and dhCer22:2 were associated with a higher T2D risk, while Cer20:0 and dhCer26:1 were associated with lower T2D risk

Summary

Introduction

Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Targeted primary cardiometabolic risk prevention requires pathway-specific biomarkers to detect the early metabolic alterations that predispose to developing these common diseases. A post hoc analysis of the PREDIMED trial suggested that CVD prevention with a Mediterranean diet intervention alleviated the higher risk of major cardiovascular events in participants with elevated ceramide levels before the intervention[14]. The actual metabolic pathways that connect these foods to cardiometabolic risk are still poorly understood Due to their potential role as disease determinants and the demonstrated sensitivity to dietary exposures, ceramides are plausibly among metabolic mediators of the effect of diet on cardiometabolic risk

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