Prioritising determinants of systemic inflammation across molecular, physiological and disease phenotypes.

Systemic inflammation is implicated in various diseases, yet its upstream determinants remain poorly examined. We conducted a large scale two-sample Mendelian randomisation (MR) study to systematically evaluate the potential causal effects of 3,213 molecular (metabolomic, proteomic), physiological and disease traits on circulating interleukin-6 (IL-6) and C-reactive protein (CRP) levels. Genetic instruments were derived from genome wide association studies and analysed using inverse variance weighted (IVW), weighted median, and MR-Egger methods with multiple testing correction. Bidirectional MR was performed to assess reverse causation. After Bonferroni correction, evidence of potential causal effects was observed for 72 traits on CRP and 9 traits on IL-6. CRP was predominantly influenced by metabolomic traits, especially lipid and fatty acid measures. Genetically proxied adiposity (body mass index and obesity), triglyceride rich lipoproteins, glycoprotein acetyls (GlycA), and apolipoprotein E increased CRP levels, whereas HDL-related cholesterols, polyunsaturated fatty acids, and glutamine decreased CRP. Most associations were consistent across MR methods, supporting the robustness of these results. As expected, IL-6 had a large effect on CRP. IL-6 was influenced by primarily adiposity and HDL-related lipid measures, with generally smaller effect sizes and limited support across sensitivity analyses. Bidirectional analyses indicated little evidence that CRP directly drives metabolic traits when restricting to cis-acting instruments, whereas genetically proxied IL-6 signalling showed consistent downstream effects on HDL particle concentration and composition. Adiposity is a shared upstream determinant of both inflammatory biomarkers, with stronger and broader effects on CRP. These findings suggest that CRP acts as an integrated downstream readout of systemic inflammatory burden, whereas IL-6 reflects a more tightly regulated and context-dependent process. Our work clarifies traits that may causally influence systemic inflammation and highlights biological pathways linking inflammation to cardiometabolic and inflammatory diseases. By mapping upstream determinants of IL-6 and CRP, we also provide a resource to prioritise key drivers for mechanistic study and therapeutic targeting. Author summaryInflammation plays a vital role in protecting the body from infection and injury but can also become chronic and consequently detrimental. Systemic inflammation is linked to many common diseases, including heart disease, diabetes, and depression. C-reactive protein and Interleukin-6 are widely used markers of inflammation which can be measured in the blood. Although these markers are often elevated in disease, it is not always clear whether they are a cause, a consequence, or a consequence of other underlying processes. In this study, we used genetic evidence from large population studies to help clarify which traits may have causal influence on levels of these inflammatory markers. By analysing thousands of potential relationships across metabolic, immune, cardiovascular, and mental health traits, we identified several metabolic processes, and related traits such as BMI and Type 2 diabetes, as key drivers of both markers of inflammation. We also found that C-reactive protein appears to reflect a broader range of biological influences than Interleukin-6. Our findings help to clarify which factors are most likely to sit upstream of systemic inflammation. This improved understanding may help guide future research aimed at preventing or reducing inflammation-related disease.