Inflammation may explain part of atherosclerotic cardiovascular disease risk conferred by elevated remnant lipoproteins: a cohort and Mendelian randomization study

BACKGROUND AND AIMS: Elevated remnant lipoproteins are a causal risk factor for atherosclerotic cardiovascular disease. We tested the hypothesis that low-grade inflammation can explain part of the increased risk of peripheral artery disease (PAD) and myocardial infarction conferred by elevated remnant lipoproteins; we also explored the causal effect of genetically elevated remnant cholesterol on inflammatory cytokine levels. METHODS: In 90,789 individuals from the Copenhagen General Population Study (2003-2015), we estimated the fraction of the association from elevated remnant cholesterol to risk of PAD and myocardial infarction explainable by low-grade inflammation using Cox regression. In 43,400 individuals from the UK Biobank, the causal effect of remnant cholesterol and LDL cholesterol on cytokine levels measured with high-throughput multiplex immunoassays was estimated using Mendelian randomization. RESULTS: During up to 15 years of follow-up, 1045 individuals were diagnosed with PAD and 1966 were diagnosed with myocardial infarction. In the association from elevated remnant cholesterol, low-grade inflammation explained 17% (95% confidence interval: 12-22%) of PAD risk and 10% (6-14%) of myocardial infarction risk. Higher remnant cholesterol causally increased levels of C-reactive protein, tumor necrosis factor (TNF), TNF-superfamily member 12, interleukin (IL)-16, IL-18, and IL-27; lowered IL-32 levels; but did not change IL-6 or IL-1β levels. CONCLUSIONS: Low-grade inflammation explained a fraction of the increased PAD and myocardial infarction risk conferred by elevated remnant lipoproteins. Elevated remnant cholesterol may induce low-grade inflammation by increasing levels of TNF rather than IL-6 and IL-1β; future studies should further investigate these potential biological pathways.