Circulating ADAM17 is associated with COVID-19 severity

Abstract

AbstractBackgroundADAM17 are emerging as an important role in the severe outcomes of COVID-19. This study aims to characterize causal relationship between ADAM17 and COVID-19.MethodsUsing mendelian randomization analyses, we examined the causal effects for circulating ADAM17 on COVID-19 outcomes using summary statistics from large genome wide association studies of ADAM17 (up to 35 559 individuals) from the Icelandic Cancer Project and deCODE genetics, critical COVID-19 (cases:13 769; controls:1 072 442), hospitalized COVID-19 (cases:32 519; controls: 2 062 805) and SARS-CoV-2 infection (cases:122 616; controls:2 475 240) from the COVID-19 Host Genetics Initiative.ResultsMendelian randomization analyses demonstrated that 1 standard deviation increase of genetically determined circulating ADAM17 at extracellular domain were associated with increasing risk of developing critical COVID-19 (odds ratio [OR]=1.26, 95% CI 1.03-1.55). Multivariable MR analysis suggested a direct causal role of circulating ADAM17 at extracellular domain on the risk of critical COVID-19 (OR=1.09; 95% CI 1.01-1.17), accounting for body mass index. Casual effects for the cytoplasmic domain of ADAM17 on COVID-19 were not observed.ConclusionOur results suggest that the increased circulating ADAM17 at extracellular domain are associated with a high risk of critical COVID-19 strengthening that of ADAM17 may contribute to the risk stratification and a therapeutic option for severe COVID-19.What is already known on this topicVarious inflammatory stimuli, as well as the SARS-CoV-2 S-protein, elevate the activity of a disintegrin and metalloproteinase 17 (ADAM17). Inhibition of ADAM17 activityin vitrohas illustrated the ability to effectively impede the infection caused by SARS-CoV-2. Nonetheless, the predictive capability of ADAM17 in predicting the severity of COVID-19 outcomes remains less certain within human populations.What this study addsUsing large genome wide association studies, Mendelian randomization study demonstrated that genetic susceptibility to the increased circulating levels of ADAM17 (extracellular domain) were associated with critical COVID-19 but not SARS-CoV-2 infection or hospitalized COVID-19.How this study might affect research, practice or policyThe study’s insights might pave the way for novel therapeutic strategies targeting ADAM17 activity. Patients with a genetic predisposition to higher ADAM17 activity might be identified and given tailored treatments.