Researchers here analyze human genetic variants in the IL-6 gene to show that reduced IL-6 activity correlates with a lower risk of cardiovascular disease. Circulating IL-6 is generally thought of as a pro-inflammatory signal, and it is a target for the development of therapies. Chronic inflammation in later life is an important contribution to dysfunction and disease, and better control over this maladaptive inflammatory reaction to the cell and tissue damage that characterizes aging is a desirable goal.
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 the IL-6 receptor (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 IL-6 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 IL-6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease, and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns related to the response to infection.
