While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Excess dietary salt contributes to inflammation and hypertension via poorly understood mechanisms. Antigen-presenting cells including DCs play a key role in regulating intestinal immune homeostasis in part by surveying the gut epithelial surface for pathogens. Previously, we found that highly reactive γ-ketoaldehydes or isolevuglandins (IsoLGs) accumulate in DCs and act as neoantigens, promoting an autoimmune-like state and hypertension. We hypothesized that excess dietary salt alters the gut microbiome leading to hypertension and this is associated with increased immunogenic IsoLG adduct formation in myeloid antigen-presenting cells. To test this hypothesis, we performed fecal microbiome analysis and measured blood pressure of healthy human volunteers with salt intake above or below the American Heart Association recommendations. We also performed 16S rRNA analysis on cecal samples of mice fed normal or high-salt diets. In humans and mice, high-salt intake was associated with changes in the gut microbiome reflecting an increase in Firmicutes, Proteobacteria, and genus Prevotella bacteria. These alterations were associated with higher blood pressure in humans and predisposed mice to vascular inflammation and hypertension in response to a subpressor dose of angiotensin II. Mice fed a high-salt diet exhibited increased intestinal inflammation, including the mesenteric arterial arcade and aorta, with a marked increase in the B7 ligand CD86 and formation of IsoLG protein adducts in CD11c ⁺ myeloid cells. Adoptive transfer of fecal material from conventionally housed high-salt diet–fed mice to germ-free mice predisposed them to increased inflammation and hypertension. These findings provide potentially novel insights into the mechanisms underlying inflammation and hypertension associated with excess dietary salt and may lead to interventions targeting the microbiome to prevent and treat this important disease.

The human microbiome has been associated with health status, and risk of disease development. While the etiology of microbiome-mediated disease remains to be fully elucidated, one mechanism may be through microbial metabolism. Metabolites produced by commensal organisms, including in response to host diet, may affect host metabolic processes, with potentially protective or pathogenic consequences. We conducted multi-omic phenotyping of healthy subjects (N = 136), in order to investigate the interaction between diet, the microbiome, and the metabolome in a cross-sectional sample. We analyzed the nutrient composition of self-reported diet (3-day food records and food frequency questionnaires). We profiled the gut and oral microbiome (16S rRNA) from stool and saliva, and applied metabolomic profiling to plasma and stool samples in a subset of individuals (N = 75). We analyzed these multi-omic data to investigate the relationship between diet, the microbiome, and the gut and circulating metabolome. On a global level, we observed significant relationships, particularly between long-term diet, the gut microbiome and the metabolome. Intake of plant-derived nutrients as well as consumption of artificial sweeteners were associated with significant differences in circulating metabolites, particularly bile acids, which were dependent on gut enterotype, indicating that microbiome composition mediates the effect of diet on host physiology. Our analysis identifies dietary compounds and phytochemicals that may modulate bacterial abundance within the gut and interact with microbiome composition to alter host metabolism.