scholarly journals Genes Contributing to Resilience and Sensitivity to Lisinopril at Old Age: Clinical Translation of GWA in Drosophila

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 683-684
Author(s):  
Mariann M Gabrawy ◽  
Nick Khosravian ◽  
George S Morcos ◽  
Meagan Jezek ◽  
Jeremy D Walston ◽  
...  
Keyword(s):  
Old Age ◽  
Wnt Signaling Pathway ◽  
Renin Angiotensin System ◽  
Human Populations ◽  
Network Analyses ◽  
Specific Effects ◽  
Conserved Genes ◽  
Genomic Studies ◽  
Drug Treatments ◽  
Ras Inhibitors

Abstract Despite impressive results in restoring physical performance in rodent models, treatment with Renin-Angiotensin System (RAS) inhibitors such as Lisinopril have highly mixed results in humans, likely, in part, due to genetic variation in human populations. To date, the genetic determinants of responses to drugs such as RAS inhibitors remain unknown. Given the complexity of the relationship between physical traits and genetic background, genomic studies which predict genotype- and age-specific responses to drug treatments in humans or vertebrate animals are difficult. Here, using 126 genetically distinct lines of Drosophila, we tested the effects of Lisinopril on climbing speed and endurance at young and old age (N=14,310). Our data show that functional response and sensitivity to Lisinopril ranges from significant protection against physical decline (8–100% faster, P< 0.0001) to increased weakness (P< 0.0001) depending on both genotype and age (P< 0.0001). Genome-wide analyses revealed little to no overlap in candidate polymorphisms influencing sensitivity between ages nor between treatments within each age. Furthermore, network analyses led to identification of evolutionarily conserved genes in the WNT signaling pathway as being significantly associated with variations in sensitivity to Lisinopril. Genetic knockdown of Axin, frizzled, nemo, and wingless, genes with human orthologs AXIN1, FZD1, NLK, and WNT1, respectively, abolished the effects of Lisinopril treatment. Our results implicate these genes as contributors to the genotype- and age-specific effects of Lisinopril treatment and as potential therapeutic targets for improvement of resiliency. Our approach should be widely applicable for identifying genomic variants that predict age-dependent responses to pharmaceutical treatments.

scholarly journals Genome-Wide Analysis in Drosophila Reveals the Genetic Basis of Variation in Age-Specific Physical Performance and Response to ACE Inhibition

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 143
Author(s):  
Mariann M. Gabrawy ◽  
Nick Khosravian ◽  
George S. Morcos ◽  
Tatiana V. Morozova ◽  
Meagan Jezek ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Physical Performance ◽  
Wnt Signaling Pathway ◽  
Renin Angiotensin System ◽  
Ace Inhibition ◽  
Human Populations ◽  
Genome Wide ◽  
Conserved Genes ◽  
Ras Inhibitors

Despite impressive results in restoring physical performance in rodent models, treatment with renin–angiotensin system (RAS) inhibitors, such as Lisinopril, have highly mixed results in humans, likely, in part, due to genetic variation in human populations. To date, the genetic determinants of responses to drugs, such as RAS inhibitors, remain unknown. Given the complexity of the relationship between physical traits and genetic background, genomic studies which predict genotype- and age-specific responses to drug treatments in humans or vertebrate animals are difficult. Here, using 126 genetically distinct lines of Drosophila melanogaster, we tested the effects of Lisinopril on age-specific climbing speed and endurance. Our data show that functional response and sensitivity to Lisinopril treatment ranges from significant protection against physical decline to increased weakness depending on genotype and age. Furthermore, genome-wide analyses led to identification of evolutionarily conserved genes in the WNT signaling pathway as being significantly associated with variations in physical performance traits and sensitivity to Lisinopril treatment. Genetic knockdown of genes in the WNT signaling pathway, Axin, frizzled, nemo, and wingless, diminished or abolished the effects of Lisinopril treatment on climbing speed traits. Our results implicate these genes as contributors to the genotype- and age-specific effects of Lisinopril treatment and because they have orthologs in humans, they are potential therapeutic targets for improvement of resiliency. Our approach should be widely applicable for identifying genomic variants that predict age- and sex-dependent responses to any type of pharmaceutical treatment.

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

scholarly journals The Efficacy of Triptolide in Preventing Diabetic Kidney Diseases: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Dongning Liang ◽  
Hanwen Mai ◽  
Fangyi Ruan ◽  
Haiyan Fu
Keyword(s):  
Systematic Review ◽  
Serum Creatinine ◽  
Blood Urea Nitrogen ◽  
Meta Analysis ◽  
Renin Angiotensin System ◽  
Risk Of Bias ◽  
Urea Nitrogen ◽  
Angiotensin System ◽  
Meta Regression ◽  
Ras Inhibitors

Ethnopharmacological Relevance: Triptolide (TP), the primary biologically active ingredient of Tripterygium wilfordii Hook F (TWHF), possesses the potential to solve the shortcomings of TWHF in treating diabetic kidney disease (DKD) in the clinic.Aim of the Study: We conducted a meta-analysis to evaluate the efficacy of TP in treating DKD and offer solid evidence for further clinical applications of TP.Materials and Methods: Eight databases (CNKI, VIP, CBM, WanFang, PubMed, Web of Science, EMBASE, and Cochrane library) were electronically searched for eligible studies until October 17, 2020. We selected animal experimental studies using TP versus renin–angiotensin system inhibitors or nonfunctional liquids to treat DKD by following the inclusion and exclusion criteria. Two researchers independently extracted data from the included studies and assessed the risk of bias with the Systematic Review Centre for Laboratory Animal Experimentation Risk of Bias tool. Fixed-effects meta-analyses, subgroup analyses, and meta-regression were conducted using RevMan 5.3 software. Inplasy registration number: INPLASY2020100042.Results: Twenty-six studies were included. Meta-analysis showed that TP significantly reduced albuminuria (14 studies; standardized mean difference SMD: −1.44 [−1.65, −1.23], I2 = 87%), urine albumin/urine creatinine ratio (UACR) (8 studies; SMD: –5.03 [–5.74, −4.33], I2 = 84%), total proteinuria (4 studies; SMD: –3.12 [–3.75, −2.49], I2 = 0%), serum creatinine (18 studies; SMD: –0.30 [–0.49, −0.12], I2 = 76%), and blood urea nitrogen (12 studies; SMD: –0.40 [–0.60, −0.20], I2 value = 55%) in DKD animals, compared to the vehicle control. However, on comparing TP to the renin–angiotensin system (RAS) inhibitors in DKD treatment, there was no marked difference in ameliorating albuminuria (3 studies; SMD: –0.35 [–0.72, 0.02], I2 = 41%), serum creatinine (3 studies; SMD: –0.07 [–0.62, 0.48], I2 = 10%), and blood urea nitrogen (2 studies; SMD: –0.35 [–0.97, 0.28], I2 = 0%). Of note, TP exhibited higher capacities in reducing UACR (2 studies; SMD: –0.66 [–1.31, −0.01], I2 = 0%) and total proteinuria (2 studies; SMD: –1.18 [–1.86, −2049], I2 = 0%). Meta-regression implicated that the efficacy of TP in reducing DKD albuminuria was associated with applied dosages. In addition, publication bias has not been detected on attenuating albuminuria between TP and RAS inhibitors after the diagnosis of DKD.Systematic Review Registration:https://clinicaltrials.gov/, identifier INPLASY2020100042

scholarly journals Efficient phasing and imputation of low-coverage sequencing data using large reference panels

2020 ◽  
Author(s):  
S. Rubinacci ◽  
D.M. Ribeiro ◽  
R. Hofmeister ◽  
O. Delaneau
Keyword(s):  
Paradigm Shift ◽  
Rare Variants ◽  
Association Studies ◽  
Cost Effective ◽  
Human Populations ◽  
Sequencing Data ◽  
Snp Arrays ◽  
Genomic Studies ◽  
Low Coverage ◽  
The Impact

AbstractLow-coverage whole genome sequencing followed by imputation has been proposed as a cost-effective genotyping approach for disease and population genetics studies. However, its competitiveness against SNP arrays is undermined as current imputation methods are computationally expensive and unable to leverage large reference panels.Here, we describe a method, GLIMPSE, for phasing and imputation of low-coverage sequencing datasets from modern reference panels. We demonstrate its remarkable performance across different coverages and human populations. It achieves imputation of a full genome for less than $1, outperforming existing methods by orders of magnitude, with an increased accuracy of more than 20% at rare variants. We also show that 1x coverage enables effective association studies and is better suited than dense SNP arrays to access the impact of rare variations. Overall, this study demonstrates the promising potential of low-coverage imputation and suggests a paradigm shift in the design of future genomic studies.

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’.

P4561Patients adherence with fixed dose combinations of renin-angiotensin-aldosterone system inhibitors in hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G A Simonyi ◽  
T Ferenci ◽  
E Finta ◽  
S Balogh ◽  
M Medvegy
Keyword(s):  
Renin Angiotensin System ◽  
Fixed Dose ◽  
Channel Blockers ◽  
Hypertensive Patients ◽  
Renin Angiotensin ◽  
Pharmacy Claims ◽  
Persistence Rate ◽  
Significant Difference ◽  
One Year ◽  
Ras Inhibitors

Abstract Introduction The latest ESC/ESH guidelines recommended fixed dose combinations (FDC) for first therapy in hypertension. Preferred two-drug combinations are a RAS (renin–angiotensin system) blocker with a CCBs (calcium channel blockers) or a diuretic. There are no available data about these FDCs adherence in hypertension. Aim To assess one year persistence of recommended FDCs (RAS-inhibitors/CCBs or diuretics) in hypertensive patients. Method Prescriptions database of National Health Insurance Found in Hungary on pharmacy-claims were analysed between October 1, 2012 and September 30, 2013. We identified patients who filled prescriptions for FDCs of RAS-inhibitors/CCBs or diuretics prescribed for the first time in hypertensive patients who have not received similar drugs during one year before. To model the persistence, the apparatus of survival analysis was used, where “survival” was the time to abandon the medication. Results 443,149 patients met the inclusion criteria. One-year persistence rate and hazard ratio (HR) of discontinuation (reference was ACEi/indapamide FDC) in patients with ACEi/CCB FDCs (n=124,154) was 44,95% (HR=0.69, [CI: 0.68–0.69], p<0.0001), ARB/HCT FDCs (n=109,707) was 42,52% (HR=0.80, [CI: 0.81–0.83], p<0.0001), ACEi/indapamide FDC (n=127,757) was 37,27% (HR=1.00, reference), ARB/CCB FDCs (n=13,542) was 29.04% (HR=1.19, [CI: 1.17–1.22], p<0.0001) and ACEi/HCT FDCs (n=67,989) was 27.47% (HR=1.17, [CI: 1.15–1.18], p<0.0001). One year peristence of FDCs Conclusions We have found significant difference between FDC s of RAS-inhibitors in hypertensive in relation of patients adherence. Our result demonstrated that ACEi/CCBs FDC therapy has the best one year persistence rate.

scholarly journals Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Keiichi Ikeda ◽  
Tsuyoshi Isaka ◽  
Kouki Fujioka ◽  
Yoshinobu Manome ◽  
Katsuyoshi Tojo
Keyword(s):  
Angiotensin Ii ◽  
Enzyme Inhibitors ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Channel Blockers ◽  
Converting Enzyme Inhibitors ◽  
Renin Angiotensin ◽  
Aldosterone Production ◽  
Ras Inhibitors

Aldosterone, a specific mineralocorticoid receptor (MR) agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II type 1 receptor antagonists (ARBs). However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS) inhibitors) gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+channel blockers (CCBs) have inhibitory actions on aldosterone production inin vitroand in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.

scholarly journals Proteinuria in frasier syndrome

2013 ◽  
Vol 141 (9-10) ◽  
pp. 685-688
Author(s):  
Amira Peco-Antic ◽  
Fatih Ozaltin ◽  
Vojislav Parezanovic ◽  
Gordana Milosevski-Lomic ◽  
Verica Zdravkovic
Keyword(s):  
Renin Angiotensin System ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Frasier Syndrome ◽  
Angiotensin System ◽  
Increased Risk ◽  
Risk Of Malignancy ◽  
End Stage ◽  
Ras Inhibitors

Introduction. Frasier syndrome (FS) is a genetic form of glomerulopathy, which results from mutations in the Wilms? tumour suppressor gene (WT1). Proteinuria in FS has been traditionally considered unresponsive to any medication and FS inevitably progresses to end stage renal failure. Case Outline. We present a patient with FS who had atypical clinical manifestation and unusual beneficial antiproteinuric response to renin-angiotensin system (RAS) inhibitors given in combination with indomethacin. After 13 years of follow-up, the patient is now 17-year old with normal renal functions and no proteinuria. Conclusion. RAS inhibitors combined with indomethacin showed beneficial effect in our patient. Thus, this combination might be the initial treatment of patients with FS. If this treatment strategy was not satisfied for at least 3 months, then CsA would be considered to be administered taking account of the nephrotoxicity and the increased risk of malignancy. Further prospective study is required to clarify this issue.

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