biostudies-literatureZhang LDeutsche ForschungsgemeinschaftGemeinnützige Hertie-StiftungDeutsche Forschungsgemeinschaft (German Research Foundation)The Munich Cluster for Systems NeurologFritz Thyssen StiftungGemeinnützige Hertie-Stiftung (Hertie Foundation)Fritz Thyssen Stiftung (Fritz Thyssen Foundation)1172-1186https://www.ebi.ac.uk/biostudies/studies/S-EPMC12436178biostudies-literatureUnknown4(9)Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on IL6R missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints. Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery diseaseNature cardiovascular researchIL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk.PMC1243617810.22.2.024MN512461526ID P1239935Xu LdeGoma EOmarov MZhang LGeorgakis MKNatarajan PfalseIL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk.Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on IL6R missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints. Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease2025-01-01T00:00:00Z2025 Sep2026-06-02T05:52:52.446Z2026-04-14T03:14:16.203ZS-EPMC124361784085883710.1038/s44161-025-00700-7