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J Am Heart Assoc ; 10(22): e022433, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1511553

ABSTRACT

Background The relationship between COVID-19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and Results Analyses primarily focused on critical COVID-19, defined as hospitalization with COVID-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID-19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID-19 and ischemic stroke (rg=0.29, false discovery rate [FDR]=0.012), body mass index (rg=0.21, FDR=0.00002), and C-reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID-19 liability 1.03, 95% CI 1.00-1.06, P-value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID-19. Conclusions These data support that liability to critical COVID-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.


Subject(s)
Brain Ischemia , COVID-19 , Ischemic Stroke , Body Mass Index , Brain Ischemia/epidemiology , Brain Ischemia/genetics , Brain Ischemia/virology , C-Reactive Protein , COVID-19/epidemiology , Genome-Wide Association Study , Humans , Inflammation , Ischemic Stroke/epidemiology , Ischemic Stroke/genetics , Ischemic Stroke/virology , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Risk Factors , Smoking
3.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-436643

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Subject(s)
Betacoronavirus/metabolism , Brain Ischemia/virology , Brain/blood supply , Diabetes Mellitus , Peptidyl-Dipeptidase A/biosynthesis , Receptors, Virus/biosynthesis , Smokers , Stroke/virology , Up-Regulation , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/pathogenicity , Brain/drug effects , Brain Ischemia/genetics , Brain Ischemia/metabolism , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Models, Animal , Disease Susceptibility , Infarction, Middle Cerebral Artery/complications , Male , Mice , Mice, Inbred C57BL , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Rats , Rats, Sprague-Dawley , Receptors, Virus/genetics , SARS-CoV-2 , Smoke/adverse effects , Stroke/genetics , Stroke/metabolism , Up-Regulation/drug effects
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