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  • El-Sayed Moustafa , J. S.; Jackson, Anne U.; Brotman, Sarah M.; Guan, Li; Villicana, Sergio; Roberts, Amy L.; Zito, Antonino; Bonnycastle, Lori; Erdos, Michael R.; Narisu, Narisu; Stringham, Heather M.; Welch, Ryan; Yan, Tingfen; Lakka, Timo; Parker, Stephen; Tuomilehto, Jaakko; Seow, Jeffrey; Graham, Carl; Huettner, Isabella; Acors, Sam; Kouphou, Neophytos; Wadge, Samuel; Duncan, Emma L.; Steves, Claire J.; Doores, Katie J.; Malim, Michael H.; Collins, Francis S.; Pajukanta, Paivi; Boehnke, Michael; Koistinen, Heikki A.; Laakso, Markku; Falchi, Mario; Bell, Jordana T.; Scott, Laura J.; Mohlke, Karen L.; Small, Kerrin S. (2022)
    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 x 10(-6)), obesity status (P = 4.81 x 10(-5)), higher serum fasting insulin (P = 5.32 x 10(-4)), BMI (P = 3.94 x 10(-4)), and lower serum HDL levels (P = 1.92 x 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 x 10(-4)) and higher proportion of macrophages (P = 2.74 x 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.