Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals. This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism. Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.

C3 is the central component of the complement system and activation of C3 via any of the three major activation pathways—the classical, the lectin and the alternative pathways—results in initiation of the terminal complement pathway and release of the anaphylatoxin C3a. Both terminal pathway activation and signalling of C3a and its inactivation product C3a-desarg via the C3a receptor and C5a-like receptor 2, respectively, can induce inflammatory, immunomodulatory and metabolic responses. C3 has been implicated in metabolic disorders, notably adiposity, dyslipidaemia, insulin resistance, liver dysfunction and diabetes, and C3 is increasingly recognised as a cardiometabolic risk factor. C3 may play a role in the macrovascular, as well as microvascular, complications of diabetes. Moreover, C3 may interact with the coagulation system and as such also contribute to a procoagulant, hypofibrinolytic and, ultimately, prothrombotic state. Recent data suggest a diabetes-dependent incorporation of C3 into fibrin clots, with concomitant effects on clot characteristics. Taken together, epidemiological and experimental evidence concordantly point to a role of complement C3 in metabolic, atherosclerotic/atherothrombotic and microangiopathic processes and further research should be directed towards the elucidation of complement function and activation in cardiometabolic disorders.