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

Shepherd, F., Slaney, C., Jones, H. J., Dardani, C., Stergiakouli, E., Sanderson, E. C. M., Hamilton, F., Rosoff, D. B., Rek, N., Gaunt, T. R., et al.

10.64898/2026.04.10.26350510 · was preprinted

biomedical

Surfaced because: matches the platform's topic region.

relevance 0.43 openness 0.00 novelty 0.31

Abstract

Background Systemic inflammation has been widely studied as a driver of disease, yet its upstream determinants remain poorly understood. Methods We performed a large-scale two-sample Mendelian randomisation study evaluating potential causal effects of 3,213 molecular, physiological and disease traits on circulating interleukin-6 and C-reactive protein. These comprised 2,923 proteomic, 249 metabolomic, 17 cardiometabolic, 7 neuropsychiatric, 8 immune-mediated inflammatory and 9 infection-related traits. Genetic instruments from genome-wide association studies were analysed using inverse variance weighted, weighted median and MR-Egger methods, with multiple-testing correction. Consistency across methods informed robustness, and bidirectional MR assessed reverse causation. Results After Bonferroni correction, 72 traits showed evidence of potential causal effects on CRP and 9 on IL-6. CRP was predominantly influenced by metabolomic traits, particularly lipid and fatty acid measures. Genetically proxied adiposity (body mass index and obesity), triglyceride-rich lipoproteins, glycoprotein acetyls (GlycA) and apolipoprotein E increased CRP, whereas HDL-related cholesterols, polyunsaturated fatty acids and glutamine decreased CRP. Most associations were consistent across MR methods. IL-6 was primarily influenced by adiposity and HDL-related lipid measures, with generally smaller effects and limited support from sensitivity analyses. Bidirectional analyses provided little evidence that CRP directly drives metabolic traits when restricted to cis-acting instruments, whereas genetically proxied IL-6 signalling showed consistent downstream effects on HDL particle concentration and composition. Conclusions Adiposity is a shared upstream determinant of both biomarkers, with stronger and broader effects on CRP. These findings suggest that CRP integrates downstream systemic inflammatory burden, whereas IL-6 reflects a more tightly regulated, context-dependent process. By shifting the focus from inflammation as a cause to inflammation as a consequence, this study maps potential causal drivers of systemic inflammation across a broad spectrum of traits and pathways, identifies pathways connecting inflammation with cardiometabolic and inflammatory diseases, and provides a resource for prioritising upstream determinants for mechanistic investigation and therapeutic targeting. 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.

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