scholarly journals Genetic Hypothesis and Pharmacogenetics Side of Renin-Angiotensin-System in COVID-19

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1044
Author(s):  
Donato Gemmati ◽  
Veronica Tisato
Keyword(s):  
Association Studies ◽  
Case Fatality ◽  
Renin Angiotensin System ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Angiotensin System ◽  
Ras Pathway ◽  
Renin Angiotensin ◽  
Transporter Family ◽  
Genetic Hypothesis

The importance of host genetics and demography in coronavirus disease 2019 (COVID-19) is a crucial aspect of infection, prognosis and associated case fatality rate. Individual genetic landscapes can contribute to understand Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) burden and can give information on how to fight virus spreading and the associated severe acute respiratory distress syndrome (ARDS). The spread and pathogenicity of the virus have become pandemic on specific geographic areas and ethnicities. Interestingly, SARS-CoV-2 firstly emerged in East Asia and next in Europe, where it has caused higher morbidity and mortality. This is a peculiar feature of SARS-CoV-2, different from past global viral infections (i.e., SARS-1 or MERS); it shares with the previous pandemics strong age- and sex-dependent gaps in the disease outcome. The observation that the severest COVID-19 patients are more likely to have a history of hypertension, diabetes and/or cardiovascular disease and receive Renin-Angiotensin-System (RAS) inhibitor treatment raised the hypothesis that RAS-unbalancing may have a crucial role. Accordingly, we recently published a genetic hypothesis on the role of RAS-pathway genes (ACE1, rs4646994, rs1799752, rs4340, rs13447447; and ACE2, rs2285666, rs1978124, rs714205) and ABO-locus (rs495828, rs8176746) in COVID-19 prognosis, suspecting inherited genetic predispositions to be predictive of COVID-19 severity. In addition, recently, Genome-Wide Association Studies (GWAS) found COVID-19-association signals at locus 3p21.31 (rs11385942) comprising the solute carrier SLC6A20 (Na+ and Cl- coupled transporter family) and at locus 9q34.2 (rs657152) coincident with ABO-blood group (rs8176747, rs41302905, rs8176719), and interestingly, both loci are associated to RAS-pathway. Finally, ACE1 and ACE2 haplotypes seem to provide plausible explanations for why SARS-CoV-2 have affected more heavily some ethnic groups, namely people with European ancestry, than Asians.

Gene variants of the renin–angiotensin system and hypertension: from a trough of disillusionment to a welcome phase of enlightenment?

2010 ◽  
Vol 118 (8) ◽  
pp. 487-506 ◽  
Author(s):  
Gavin R. Norton ◽  
Richard Brooksbank ◽  
Angela J. Woodiwiss
Keyword(s):  
Association Studies ◽  
Large Population ◽  
Renin Angiotensin System ◽  
Human Populations ◽  
Incomplete Penetrance ◽  
Gene Variants ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
The Impact

There is substantial evidence to suggest that BP (blood pressure) is an inherited trait. The introduction of gene technologies in the late 1980s generated a sharp phase of over-inflated prospects for polygenic traits such as hypertension. Not unexpectedly, the identification of the responsible loci in human populations has nevertheless proved to be a considerable challenge. Common variants of the RAS (renin–angiotensin system) genes, including of ACE (angiotensin-converting enzyme) and AGT (angiotensinogen) were some of the first shown to be associated with BP. Presently, ACE and AGT are the only gene variants with functional relevance, where linkage studies showing relationships with hypertension have been reproduced in some studies and where large population-based and prospective studies have demonstrated these genes to be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in other linkage and association studies has generated scepticism that only a concerted effort to attempt to explain will rectify. Without these explanations, it is unlikely that this knowledge will translate into the clinical arena. In the present review, we show that many of the previous concerns in the field have been addressed, but we also argue that a considerable amount of careful thought is still required to achieve enlightenment with respect to the role of RAS genes in hypertension. We discuss whether the previously identified problems of poor study design have been completely addressed with regards to the impact of ACE and AGT genes on BP. In the context of RAS genes, we also question whether the significance of ‘incomplete penetrance’ through associated environmental, phenotypic or physiological effects has been duly accounted for; whether appropriate consideration has been given to epistatic interactions between genes; and whether future RAS gene studies should consider variation across the gene by evaluating ‘haplotypes’.

scholarly journals Renin–angiotensin system blockers, risk of SARS-CoV-2 infection and outcomes from CoViD-19: systematic review and meta-analysis

2020 ◽  
Author(s):  
Matthew M Y Lee ◽  
Kieran F Docherty ◽  
Naveed Sattar ◽  
Neil Mehta ◽  
Ankur Kalra ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ace Inhibitor ◽  
Meta Analysis ◽  
Intensive Therapy ◽  
Case Fatality ◽  
Renin Angiotensin System ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Renin Angiotensin System Blockers

Abstract Aims This meta-analysis provides summary odds ratio (OR) estimates for associations between treatment with (vs. without) renin–angiotensin system blockers and risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and coronavirus disease 2019 (CoViD-19) severity (including case-fatality) in patients with hypertension, and in all patients (irrespective of hypertension). Methods and results PubMed, EMBASE, Web of Science, Google Scholar, medRxiv, and SSRN were searched (2 May 2020 to 12 August 2020) for non-randomized observational CoViD-19 studies. Event/patient numbers were extracted, comparing angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) treatment (and each separately), to treatment with neither drug, for the outcomes: (i) likelihood of SARS-CoV-2 infection; (ii) CoViD-19 severity [including hospitalization, intensive therapy unit (ITU), ventilation]; (iii) case-fatality. The risk of bias was assessed (ROBINS-I). Random-effects meta-analysis estimates were pooled. Eighty-six studies including 459 755 patients (103 317 with hypertension), were analysed. In patients with hypertension, ACE inhibitor or ARB treatment was not associated with a greater likelihood of SARS-CoV-2 infection in 60 141 patients (OR 1.06, 95% CI 0.99–1.14), hospitalization in 5925 patients (OR 0.90, 0.62–1.31), ITU in 7218 patients (OR 1.06, 0.73–1.56), ventilation (or ITU/ventilation/death) in 13 163 patients (OR 0.91, 0.72–1.15) or case-fatality in 18 735 patients with 2893 deaths (OR 0.75, 0.61–0.92). Conclusion Angiotensin-converting enzyme inhibitors and ARBs appear safe in the context of SARS-CoV-2 infection and should not be discontinued. PROSPERO registration number CRD42020186996.

Genetics of ischemic stroke: where are we now?

2011 ◽  
Vol 152 (12) ◽  
pp. 455-463 ◽  
Author(s):  
Anita Maász ◽  
Zoltán Szolnoki ◽  
László Balikó ◽  
Béla Melegh
Keyword(s):  
Ischemic Stroke ◽  
Genetic Variants ◽  
Association Studies ◽  
Renin Angiotensin System ◽  
Cerebrovascular Diseases ◽  
Genome Wide Association Studies ◽  
Angiotensin System ◽  
New Approach ◽  
Genome Wide ◽  
Genes Encoding

As stroke is the third leading cause of death after heart failure and tumors worldwide, cerebrovascular diseases reached substantial attention. In the past few years, significant progression has been seen in identification of genetic variants in the background of stroke and other cerebrovascular and cardiovascular events. Examination of these variants is a new approach to recognize pathogenesis of disorders that hopefully helps in future prevention and prospects of screening and, optimistically, it contributes to special care of patients susceptible for stroke. In the background of ischemic stroke several genetic variants have been identified, which localize in genes encoding proteins involved in hemostasis, renin-angiotensin system and lipid metabolism. The number of these variants exponentially increases permanently due to rapid spreading of genome wide association studies. The goal of this review is to summarize the results of genetic studies on ischemic stroke. Here the authors focus on genetic variants which can have major role in personalized medicine and prevention of stroke. Orv. Hetil., 2011, 152, 455–463.

scholarly journals The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1704 ◽  
Author(s):  
Loris Zamai
Keyword(s):  
Positive Feedback ◽  
Experimental Studies ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Ras Pathway ◽  
Renin Angiotensin ◽  
Renin Inhibitors ◽  
Yin And Yang ◽  
Zinc Metalloproteases

The article describes the rationale for inhibition of the renin-angiotensin system (RAS) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent positive feedback-loop mechanisms. Based purely on experimental studies in which RAS pathway inhibitors were administered in vivo to humans/rodents, a reasonable hypothesis of using inhibitors that block both ACE and ACE2 zinc metalloproteases and their downstream pathways in COVID-19 patients will be proposed. In particular, metal (zinc) chelators and renin inhibitors may work alone or in combination to inhibit the positive feedback loops (initially triggered by SARS-CoV-2 and subsequently sustained by hypoxia independently on viral trigger) as both arms of renin-angiotensin system are upregulated, leading to critical, advanced and untreatable stages of the disease.

scholarly journals Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Siew Mei Joyce-Tan ◽  
Shamsul Mohd Zain ◽  
Munavvar Zubaid Abdul Sattar ◽  
Nor Azizan Abdullah
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renin Angiotensin System ◽  
Gene Interactions ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Angiotensin System ◽  
Renin Angiotensin

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls forAGTvariants (P=0.05) but not forACEandAGTR1. Haplotype TCG of theAGTwas associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permutedP=0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of theAGTvariants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

Involvement of the renin–angiotensin system in abdominal and thoracic aortic aneurysms

2012 ◽  
Vol 123 (9) ◽  
pp. 531-543 ◽  
Author(s):  
Hong Lu ◽  
Debra L. Rateri ◽  
Dennis Bruemmer ◽  
Lisa A. Cassis ◽  
Alan Daugherty
Keyword(s):  
Animal Models ◽  
Aortic Rupture ◽  
Association Studies ◽  
Renin Angiotensin System ◽  
Pharmacological Therapy ◽  
Aortic Aneurysms ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Thoracic Aortic Aneurysms

Aortic aneurysms are relatively common maladies that may lead to the devastating consequence of aortic rupture. AAAs (abdominal aortic aneurysms) and TAAs (thoracic aortic aneurysms) are two common forms of aneurysmal diseases in humans that appear to have distinct pathologies and mechanisms. Despite this divergence, there are numerous and consistent demonstrations that overactivation of the RAS (renin–angiotensin system) promotes both AAAs and TAAs in animal models. For example, in mice, both AAAs and TAAs are formed during infusion of AngII (angiotensin II), the major bioactive peptide in the RAS. There are many proposed mechanisms by which the RAS initiates and perpetuates aortic aneurysms, including effects of AngII on a diverse array of cell types and mediators. These experimental findings are complemented in humans by genetic association studies and retrospective analyses of clinical data that generally support a role of the RAS in both AAAs and TAAs. Given the lack of a validated pharmacological therapy for any form of aortic aneurysm, there is a pressing need to determine whether the consistent findings on the role of the RAS in animal models are translatable to humans afflicted with these diseases. The present review compiles the recent literature that has shown the RAS as a critical component in the pathogenesis of aortic aneurysms.

scholarly journals Dipeptidyl peptidase 3 modulates the renin–angiotensin system in mice

2020 ◽  
Vol 295 (40) ◽  
pp. 13711-13723 ◽  
Author(s):  
Shalinee Jha ◽  
Ulrike Taschler ◽  
Oliver Domenig ◽  
Marko Poglitsch ◽  
Benjamin Bourgeois ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Dipeptidyl Peptidase ◽  
Amino Acid Residues ◽  
Angiotensin System ◽  
Ras Pathway ◽  
Renin Angiotensin ◽  
Cell Defense ◽  
Angiotensin Peptides ◽  
Dipeptidyl Peptidase 3

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase involved in degrading oligopeptides with 4–12 amino acid residues. It has been associated with several pathophysiological processes, including blood pressure regulation, pain signaling, and cancer cell defense against oxidative stress. However, the physiological substrates and the cellular pathways that are potentially targeted by DPP3 to mediate these effects remain unknown. Here, we show that global DPP3 deficiency in mice (DPP3−/−) affects the renin–angiotensin system (RAS). LC–MS–based profiling of circulating angiotensin peptides revealed elevated levels of angiotensin II, III, IV, and 1–5 in DPP3−/− mice, whereas blood pressure, renin activity, and aldosterone levels remained unchanged. Activity assays using the purified enzyme confirmed that angiotensin peptides are substrates for DPP3. Aberrant angiotensin signaling was associated with substantially higher water intake and increased renal reactive oxygen species formation in the kidneys of DPP3−/− mice. The metabolic changes and altered angiotensin levels observed in male DPP3−/− mice were either absent or attenuated in female DPP3−/− mice, indicating sex-specific differences. Taken together, our observations suggest that DPP3 regulates the RAS pathway and water homeostasis by degrading circulating angiotensin peptides.

scholarly journals COVID-19: age, Interleukin-6, C-Reactive Protein and lymphocytes as key clues from a multicentre retrospective study in Spain

2020 ◽  
Author(s):  
Aurora Jurado ◽  
María C. Martín ◽  
Cristina Abad-Molina ◽  
Antonio Orduña ◽  
Alba Martínez ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Interleukin 6 ◽  
Clinical Laboratory ◽  
Case Fatality ◽  
Renin Angiotensin System ◽  
Local Health ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Age Related ◽  
Renin Angiotensin System Blockers

ABSTRACTBackgroundSARS-CoV-2 infection has widely spread to the hugest public health challenge to date, COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. Spanish case-fatality rate is 11.94%, far higher to those reported in Asia or by other European countries. A multicenter retrospective study was performed of demographic, clinical, laboratory and immunological features of 574 Spanish COVID-19 hospitalized patients and their outcomes. The use of use of renin-angiotensin system blockers was also analyzed as a risk factor.ResultsIn this study, 27.7% of cases presented a mild curse, 42% a moderate one and for 30.3% of cases, the course was severe. Ages ranged from 18 to 98 (average 63.2). Fifty eight percent (58.9%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19 and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of renin-angiotensin system blockers was associated with moderate or mild disease courses.ConclusionsAge and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for immune system effectors severity-related hampering. Adaptive immunity would go exhausted and a huge ineffective and almost deleterious innate response would account for COVID-19 severity. Renin-angiotensin system blockers treatment in hypertensive patients has a protective effect as regarding COVID-19 severity.

The renin–angiotensin system and physical performance

2003 ◽  
Vol 31 (6) ◽  
pp. 1286-1289 ◽  
Author(s):  
J. Payne ◽  
H. Montgomery
Keyword(s):  
Physical Performance ◽  
Association Studies ◽  
Renin Angiotensin System ◽  
Genetic Influences ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Disease States ◽  
Candidate Gene Association ◽  
Angiotensin Converting Enzyme Genotype

Many of us recognize that some individuals seem ‘gifted’ in sporting ability. We may also have noted the association of such elite performance with past parental success, recognizing intuitively the role of inherited traits. With the expansion of molecular biology and associated technologies, we now find ourselves better able to explore these genetic influences. This article examines the role of the renin–angiotensin system in regulating physical performance, based on data arising from candidate gene-association studies. In particular, the association of angiotensin-converting enzyme genotype with performance-related phenotypes will be addressed. Finally, we will briefly discuss the applicability of this data to disease states such as heart failure.

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