Factor V is an immune inhibitor that is expressed at increased levels in leukocytes of patients with severe Covid-19 (preprint)

Severe Covid-19 is associated with elevated plasma Factor V (FV) and increased risk of thromboembolism. We report that neutrophils, T regulatory cells (Tregs), and monocytes from patients with severe Covid-19 express FV, and expression correlates with T cell lymphopenia. In vitro full length FV, but not FV activated by thrombin cleavage, suppresses T cell proliferation. Increased and prolonged FV expression by cells of the innate and adaptive immune systems may contribute to lymphopenia in severe Covid-19. Activation by thrombin destroys the immunosuppressive properties of FV. Anticoagulation in Covid-19 patients may have the unintended consequence of suppressing the adaptive immune system.

ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: a Mendelian randomization study (preprint)

ObjectivesTo use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. DesignTwo-sample Mendelian randomization (MR) analysis. SettingSummary-level genetic association data. ParticipantsParticipants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants). Main outcomes and measuresLung ACE2 and TMPRSS2 expression and plasma ACE2 levels. ResultsThere were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4x10-4) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes. ConclusionsThis study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification. Summary boxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. C_LIO_LISerine protease TMPRSS2 is involved in priming the SARS-CoV-2 spike protein for cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor. C_LIO_LIExpression of ACE2 and TMPRSS2 in the lung epithelium might have implications for risk of SARS-CoV-2 infection and severity of COVID-19. C_LI What this study addsO_LIWe used human genetic variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 expression and circulating ACE2 levels. C_LIO_LIOur findings do not support the hypothesis that ACE inhibitors have effects on ACE2 expression. C_LIO_LIWe found some support for an association of genetic liability to type 2 diabetes mellitus with higher lung ACE2 expression and plasma ACE2 levels, but evidence was inconsistent across studies. C_LI