ACE inhibition and cardiometabolic risk factors, lung <i>ACE2</i> and <i>TMPRSS2</i> gene expression, and plasma ACE2 levels: a Mendelian randomization study
Bibliographic record
Abstract
Abstract Objectives To use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. Design Two-sample Mendelian randomization (MR) analysis. Setting Summary-level genetic association data. Participants Participants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants). Main outcomes and measures Lung ACE2 and TMPRSS2 expression and plasma ACE2 levels. Results There were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4×10 −4 ) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes. Conclusions This study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification. Summary boxes What is already known on this topic Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. Serine protease TMPRSS2 is involved in priming the SARS-CoV-2 spike protein for cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor. Expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for risk of SARS-CoV-2 infection and severity of COVID-19. What this study adds We used human genetic variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 expression and circulating ACE2 levels. Our findings do not support the hypothesis that ACE inhibitors have effects on ACE2 expression. We found some support for an association of genetic liability to type 2 diabetes mellitus with higher lung ACE2 expression and plasma ACE2 levels, but evidence was inconsistent across studies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".