ACE2 expression in adipose tissue is associated with cardio-metabolic risk factors and cell type composition—implications for COVID-19
Julia S. El-Sayed Moustafa, Anne Jackson, Sarah M. Brotman, Li Guan, Sergio Villicaña, Amy L. Roberts, Antonino Zito, Lori L. Bonnycastle, Michael R. Erdos, Narisu Narisu, Heather M. Stringham, Ryan Welch, Tingfen Yan, Timo A. Lakka, Stephen C.J. Parker, Jaakko Tuomilehto, Jeffrey Seow, Carl Graham, Isabella Huettner, Sam Acors, Neophytos Kouphou, Samuel Wadge, Emma L. Duncan, Claire J. Steves, Katie J. Doores, Michael H. Malim, Francis S. Collins, Päivi Pajukanta, Michael Boehnke, Heikki A. Koistinen, Markku Laakso, Mario Falchi, Jordana T. Bell, Laura J. Scott, Karen L. Mohlke, Kerrin S. Small
Abstract
Abstract Background COVID-19 severity varies widely. Although some demographic and cardio-metabolic factors, including age and obesity, are associated with increasing risk of severe illness, the underlying mechanism(s) are uncertain. Subjects/methods In a meta-analysis of three independent studies of 1471 participants in total, we investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 ( ACE2 ), measured by RNA-Seq, which acts as a receptor for SARS-CoV-2 cellular entry. Results Lower adipose tissue ACE2 expression was associated with multiple adverse cardio-metabolic health indices, including type 2 diabetes (T2D) ( P = 9.14 × 10 −6 ), obesity status ( P = 4.81 × 10 −5 ), higher serum fasting insulin ( P = 5.32 × 10 −4 ), BMI ( P = 3.94 × 10 −4 ), and lower serum HDL levels ( P = 1.92 × 10 −7 ). ACE2 expression was also associated with estimated proportions of cell types in adipose tissue: lower expression was associated with a lower proportion of microvascular endothelial cells ( P = 4.25 × 10 −4 ) and higher proportion of macrophages ( P = 2.74 × 10 −5 ). Despite an estimated heritability of 32%, we did not identify any proximal or distal expression quantitative trait loci (eQTLs) associated with adipose tissue ACE2 expression. Conclusions Our results demonstrate that individuals with cardio-metabolic features known to increase risk of severe COVID-19 have lower background ACE2 levels in this highly relevant tissue. Reduced adipose tissue ACE2 expression may contribute to the pathophysiology of cardio-metabolic diseases, as well as the associated increased risk of severe COVID-19.