Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic Profile

Interleukin-6 (IL6) signaling is a key inflammatory pathway involved in activation and regulation of immune responses, tissue regeneration, and metabolism. 1 Although IL6 receptor (IL6R) inhibitors are already in use for the treatment of autoimmune diseases, 2 accumulating evidence supports a broader role of IL6 signaling in human disease.2,3 Still, it remains unknown whether IL6R blockade could be effectively repurposed for the treatment or prevention of diseases beyond current indications.We recently identified 7 genetic variants in the IL6R locus showing similar effects on upstream (soluble IL6R and IL6) and downstream (C-reactive protein and fibrinogen) molecules in the IL6-signaling cascade as those derived from clinical trials for IL6R inhibitors. 4 Here, to systematically explore potential repurposing opportunities and unknown side effects associated with IL6R blockade, we used these variants as proxies of IL6-signaling downregulation and examined widespread effects in a phenome-wide association study.Specifically, we analyzed 1428 clinical outcomes in up to 339 256 White British individuals from the UK Biobank study and validated the identified signals in a meta-analysis with the Penn Medicine (10 244 individuals) and the BioMe (9054 individuals) Biobanks of European American individuals.We further analyzed 366 disease-related biomarkers including hematologic, biochemical, metabolomic, inflammatory, immunologic, hemodynamic, and anthropometric traits in the UK Biobank and phenotype-specific genetic consortia.We pooled the single-nucleotide polymorphism-specific effects using Mendelian randomization (MR) analyses scaled to the effects of tocilizumab, an IL6R-targeting monoclonal antibody.A detailed description of methods and summary statistics for the presented analyses are provided elsewhere.5 Supporting data for the UK Biobank analyses are available online, 5 whereas supporting data from the Penn Medicine Biobank and BioMe Biobank are available on request to the principal investigators of the study.All participants provided informed consent, and all studies obtained institutional review board approval as detailed elsewhere.5 There were 35 clinical outcomes reaching statistical significance (false discovery rate<0.05;P<0.0017) in the primary inverse variance-weighted MR analyses; 33 of them showed no evidence of heterogeneity (P>0.10) while exhibiting consistent associations (same direction, P<0.05) in sensitivity analyses (weighted-median MR, analyses restricted to 3 single-nucleotide polymorphisms within IL6R).In the meta-analysis of the UK Biobank with the Penn Medicine BioBank and BioMe Biobanks, 16 of the 24 outcomes with sufficient statistical power for validation remained significant (P<0.0017; Figure , A).There were significant associations of genetically downregulated IL6 signaling with lower risk of several atherosclerotic phenotypes including ischemic heart disease (odds ratio [OR], 0.84 [95% CI, 0.77-0.90])and abdominal aortic aneurysm (OR, 0.44 [95% CI, 0.29-0.67]),as well as with lower risk of type 2 diabetes (OR, 0.80 [95% CI, 0.73-0.88]).Conversely, we found associations of genetically downregulated IL6 Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic