key: cord-0903964-07ryzlt0 authors: Kornilov, S. A.; Lucas, I.; Jade, K.; Dai, C. L.; Lovejoy, J. C.; Magis, A. T. title: Plasma levels of soluble ACE2 are associated with sex, Metabolic Syndrome, and its biomarkers in a large cohort, pointing to a possible mechanism for increased severity in COVID-19 date: 2020-06-12 journal: nan DOI: 10.1101/2020.06.10.20127969 sha: e367f0da92572ea5d89287c3ab9ea0965c5f4377 doc_id: 903964 cord_uid: 07ryzlt0 We examined the associations between plasma concentrations of soluble ACE2 and biomarkers of Metabolic Syndrome in a large (N=2,051) sample of individuals who participated in a commercial wellness program and who underwent deep molecular phenotyping. sACE2 levels were significantly higher in men, compared to women, and in individuals with Metabolic Syndrome, compared to controls. sACE2 levels showed reliable associations with all individuals components of Metabolic Syndrome, including obesity, hypertension, insulin resistance, hyperlipidemia, and as well as markers of liver damage. This profile of associations was statistically significantly stronger in men, compared to women, and suggests that preexisting cardiometabolic conditions might confer increased severity of symptoms in some COVID-19 patients through increased expression of ACE2 in the liver. statistically significantly stronger in men, compared to women, and points to preexisting (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. Patients who are at high risk for mortality from COVID-19, the disease caused by severe acute 37 respiratory syndrome coronavirus 2 (SARS-CoV-2), are more likely to be older and male, and to 38 have chronic diseases such as hypertension, diabetes, cardiovascular, and chronic lung 39 disease [1, 2] . Although the mechanisms behind these associations are poorly understood, this 40 increased risk could be partly associated with increased expression of the cellular receptor of 41 SARS-CoV-2, angiotensin-converting enzyme-2 (ACE2), which is found at elevated levels in 42 older individuals, men, and in cardiovascular and inflammatory conditions [3, 4] . ACE2 maintains 43 homeostasis of the renin-angiotensin system and converts angiotensin II to angiotensin 1-7, 44 which has vasodilatory and anti-inflammatory properties. It occurs in a membrane bound form 45 (mACE2), highly expressed in heart, airways, kidney, and liver tissue, and in an enzymatically 46 active soluble form (sACE2) that is generated in response to inflammatory signals and disease 47 via mACE2 shedding into the blood where it normally is found at low levels in healthy 48 individuals. We interrogated the associations between plasma concentrations of sACE2 and biomarkers of 51 Metabolic Syndrome (Body Mass Index, BMI; blood pressure; glycemic markers, and lipid 52 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. Confirming results from recent studies [3,4], we found higher plasma sACE2 levels in men 66 compared to women (P=2x10 -16 ), and in older individuals (P=8.6x10 -11 ), with the age association 67 more pronounced in women (for the interaction, P int =0.02). We found higher levels of sACE2 in 68 post-menopausal women, compared to pre-menopausal women (P=0.02; see Figure 1 ). Individuals who met World Health Organization's (WHO) diagnostic criteria for MetS (N=171) 71 displayed elevated plasma sACE2 levels compared to controls (N=1,880; P=4.7x10 -5 ), and the 72 effect was stronger in men (P int =8.9x10 -5 ). We found all of MetS component biomarkers to be 73 positively associated with plasma sACE2 (see Figure 2 ). The associations were significantly 74 stronger in men for biomarkers of obesity and adiposity (BMI, P int =0.0123; leptin, P int =0.0342), 75 insulin resistance and hyperglycemia (HbA1c, P int =0.0368; HOMA-IR, P int =0.042), as well as 76 triglycerides (P int =0.0134) and serum hsCRP (P int =0.041). Among examined biomarkers, we 77 found the strongest association between sACE2 and GGT (P=3.44x10 -90 ), an enzyme that is an 78 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 12, 2020. The dataset supporting the conclusions of this article is available from the authors upon request. Predictors of mortality in hospitalized COVID-19 patients: 143 A systematic review and meta-analysis Diabetes is a risk factor for the progression and prognosis of 145 COVID-19 Age and sex 147 differences in soluble ACE2 may give insights for COVID-19 Circulating plasma concentrations of 149 angiotensin-converting enzyme 2 in men and women with heart failure and effects of 150 renin-angiotensin-aldosterone inhibitors Genetic Predisposition Impacts Clinical Changes 152 in a Upregulation of hepatic Upregulation of hepatic 154 angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental 155 biliary fibrosis No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted The authors were previously employed by Arivale, Inc, and held stock options in the company. Arivale is now closed. Funding 133 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted June 12, 2020.