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Genetically downregulated interleukin-6 signaling is associated with a favorable cardiometabolic profile: a phenome-wide association study

By Marios K. Georgakis, Rainer Malik, Xue Li, Dipender Gill, Michael G. Levin, Ha My T Vy, Renae Judy, Marylyn Ritchie, Shefali S. Verma, Regeneron Genetics Center, Girish N. Nadkarni, Scott M. Damrauer, Evropi Ī¤heodoratou, Martin Dichgans

Posted 03 Nov 2020
medRxiv DOI: 10.1101/2020.10.28.20220822

BackgroundInterleukin-6 (IL6) signaling is a key inflammatory pathway widely implicated in the pathogenesis of multiple diseases including autoimmune, vascular, and metabolic disorders. While IL6-receptor (IL6R) inhibitors are already in use for the treatment of autoimmune diseases, their repurposing potential and safety profile is still debated. MethodsWe used 7 genetic variants at the IL6R locus as proxies for IL6 signaling downregulation and explored their effects on 1,428 clinical outcomes in a phenome-wide association study (PheWAS) using data from the UK Biobank (339,256 unrelated individuals). Significant associations were meta-analyzed with data from the Penn Medicine (10,244 individuals) and BioMe (9,054 individuals) Biobanks for validation. We further investigated associations between genetically downregulated IL6 signaling and 366 biomarkers and endophenotypes of human disease in the UK Biobank and other phenotype-specific consortia. All associations were examined by Mendelian randomization (MR) analyses scaled to the effects of tocilizumab, a monoclonal antibody targeting IL6R. ResultsThe PheWAS-MR analyses showed significant associations with 16 clinical outcomes and 17 biomarkers following correction for multiple comparisons. Genetically downregulated IL6 signaling was associated with a lower risk of several atherosclerotic phenotypes including ischemic heart disease (OR: 0.84, 95%CI: 0.77-0.90) and abdominal aortic aneurysm (OR: 0.44, 95%CI: 0.29-0.67). We further found significant associations with lower risk of type 2 diabetes (OR: 0.80, 95%CI: 0.73-0.88), lower glycated hemoglobin A1c (HbA1c) levels (beta: -0.07, 95%CI: -0.08 to -0.05), and higher HDL-cholesterol levels (beta: 0.04, 95%CI: 0.02-0.06). In accord with clinical trials examining pharmacological IL6 blockade, genetically downregulated IL6 signaling was associated with higher risk of neutropenia and bacterial infections (cellulitis and urinary tract infections) and with higher hemoglobin concentrations. We further found significant associations with higher risk of atopic dermatitis and higher levels of the pro-allergic cytokine interleukin-4. ConclusionsGenetic IL6 signaling downregulation associates with a lower risk of vascular outcomes and a more favorable cardiometabolic profile. These findings further support a repurposing of IL6R blockade for lowering cardiovascular risk while also informing on potential side effects.

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