Abstract
Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10−4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic [1]
It has been speculated that the angiotensinconverting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) classes of antihypertensive medication that are more commonly prescribed in patients with cardiometabolic risk factors might affect the expression of angiotensin-converting enzyme 2 (ACE2) and affect susceptibility to SARS-CoV-2 infection and severity of consequent 3 COVID-19 [14,15,16,17,18,19,20]
The aim of this study was to apply Mendelian randomization to investigate whether ACE2 and TMPRSS2 gene expression in the lung and circulating levels of ACE2 in the plasma are associated with (i) genetic variants in the angiotensin-converting enzyme (ACE) gene region that can be considered as proxies for the effect of ACEi drugs and (ii) genetic variants related to cardiometabolic risk factors
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic [1]. COVID-19 patients most frequently present with respiratory tract infection symptoms [6,7,8,9,10,11] It follows that the expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19 [2,12,13]. It has been speculated that the angiotensinconverting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) classes of antihypertensive medication that are more commonly prescribed in patients with cardiometabolic risk factors might affect the expression of ACE2 and affect susceptibility to SARS-CoV-2 infection and severity of consequent 3 COVID-19 [14,15,16,17,18,19,20]. This could be used to inform optimal medication use and strategies for shielding vulnerable individuals, as well as improving the evidence base for public health campaigns
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