Circulating ADAM17 is associated with COVID-19 severity

Background ADAM17 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. Methods Using 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. Results Mendelian 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. Conclusion Our 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 topic Various inflammatory stimuli, as well as the SARS-CoV-2 S-protein, elevate the activity of a disintegrin and metalloproteinase 17 (ADAM17). Inhibition of ADAM17 activity in vitro has 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 adds Using 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 policy The 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from the Kockska foundation, ALF Grants Region Skane, the Bo and Kerstin Hjelt Diabetes Foundation, Swedish Stroke Association, Soderstrom Konig Foundation, the Swedish Research Council, the Swedish Heart and Lung Foundation, Skane University Hospital funds, Swedish Society for Medical Research, Swedish Stroke Association, Emil and Wera Cornell foundation, Crafoord foundation, The Swedish Society of Medicine, Diabetes foundation, Southern Sweden Regional Research Funding, Albert Pahlssons foundation, Lund University Diabetes Center (Swedish Research Council,Strategic Research Area Exodiab Dnr 20091039, Linnaeus grant Dnr 349200623 and the Swedish Foundation for Strategic Research Dnr IRC15006) and Ake Wiberg foundation. The Knut and Alice Wallenberg Foundation, the Medical Faculty at Lund University, and Region Skane are acknowledged for generous financial support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors