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Role of Genomics in the Management of Hypertension

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2018) | Viewed by 102547

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Special Issue Editors

Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Turin, 10126 Turin, Italy
Interests: primary aldosteronism; secondary hypertension; familial hypertension; adrenal glands; renin-angiotensin system
Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Turin, 10126 Turin, Italy
Interests: genetic hypertension; endocrine hypertension; aldosterone-producing adenoma; adrenal vein sampling; juvenile hypertension

Special Issue Information

Dear Colleagues,

Hypertension is the most important modifiable risk factor for cardiovascular disease and affects about 1 billion people worldwide. Notwithstanding major advances in understanding the pathophysiology of hypertension, it remains largely uncontrolled in the general population. Twin and family studies have demonstrated that 30–50% of the individual risk comes from genetic factors and a family history of hypertension increases the risk of developing high blood pressure levels by four times.

Over the last few decades, a wealth of genetic and genomics studies have shed new light on the pathogenesis of hypertension. Identification of Mendelian syndromes has provided important insights into the pathophysiology of hypertension and enabled effective etiological therapy; genome-wide association studies have identified new potentially involved genes and pharmacologically targetable pathways.

This Special Issue focuses on “Role of Genomics in the Management of Hypertension”. We warmly welcome submissions, including original papers and reviews, on this widely discussed topic.

Assoc. Prof. Paolo Mulatero
Dr. Silvia Monticone
Guest Editors

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Keywords

  • monogenic hypertension
  • genomics
  • genome-wide association studies
  • epigenetics
  • pharmacogenomics

Published Papers (12 papers)

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Research

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13 pages, 4577 KiB  
Article
Role of Cryptochrome-1 and Cryptochrome-2 in Aldosterone-Producing Adenomas and Adrenocortical Cells
by Martina Tetti, Isabella Castellano, Francesca Veneziano, Corrado Magnino, Franco Veglio, Paolo Mulatero and Silvia Monticone
Int. J. Mol. Sci. 2018, 19(6), 1675; https://doi.org/10.3390/ijms19061675 - 05 Jun 2018
Cited by 6 | Viewed by 3149
Abstract
Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3β-hydroxyl-steroid dehydrogenase (Hsd3b6), the murine counterpart to the human type I 3β-hydroxyl-steroid dehydrogenase (HSD3B1) gene. In the [...] Read more.
Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3β-hydroxyl-steroid dehydrogenase (Hsd3b6), the murine counterpart to the human type I 3β-hydroxyl-steroid dehydrogenase (HSD3B1) gene. In the present study, we evaluated the role of CRY1 and CRY2 genes, and their potential interplay with HSD3B isoforms in adrenal pathophysiology in man. Forty-six sporadic aldosterone-producing adenomas (APAs) and 20 paired adrenal samples were included, with the human adrenocortical cells HAC15 used as the in vitro model. In our cohort of sporadic APAs, CRY1 expression was 1.7-fold [0.75–2.26] higher (p = 0.016), while CRY2 showed a 20% lower expression [0.80, 0.52–1.08] (p = 0.04) in APAs when compared with the corresponding adjacent adrenal cortex. Type II 3β-hydroxyl-steroid dehydrogenase (HSD3B2) was 317-fold [200–573] more expressed than HSD3B1, and is the main HSD3B isoform in APAs. Both dehydrogenases were more expressed in APAs when compared with the adjacent cortex (5.7-fold and 3.5-fold, respectively, p < 0.001 and p = 0.001) and HSD3B1 was significantly more expressed in APAs composed mainly of zona glomerulosa-like cells. Treatment with angiotensin II (AngII) resulted in a significant upregulation of CRY1 (1.7 ± 0.25-fold, p < 0.001) at 6 h, and downregulation of CRY2 at 12 h (0.6 ± 0.1-fold, p < 0.001), through activation of the AngII type 1 receptor. Independent silencing of CRY1 and CRY2 genes in HAC15 cells resulted in a mild upregulation of HSD3B2 without affecting HSD3B1 expression. In conclusion, our results support the hypothesis that CRY1 and CRY2, being AngII-regulated genes, and showing a differential expression in APAs when compared with the adjacent adrenal cortex, might be involved in adrenal cell function, and in the regulation of aldosterone production. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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Review

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17 pages, 334 KiB  
Review
Genetics of Hypertension in African Americans and Others of African Descent
by Mihail Zilbermint, Fady Hannah-Shmouni and Constantine A. Stratakis
Int. J. Mol. Sci. 2019, 20(5), 1081; https://doi.org/10.3390/ijms20051081 - 02 Mar 2019
Cited by 37 | Viewed by 13416
Abstract
Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of [...] Read more.
Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
11 pages, 1139 KiB  
Review
Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases
by Marco Simonini, Paola Casanova, Lorena Citterio, Elisabetta Messaggio, Chiara Lanzani and Paolo Manunta
Int. J. Mol. Sci. 2018, 19(7), 1948; https://doi.org/10.3390/ijms19071948 - 03 Jul 2018
Cited by 14 | Viewed by 3976
Abstract
The endogenous ouabain (EO) is a steroid hormone secreted by the adrenal gland with cardio-tonic effects. In this article, we have reviewed and summarized the most recent reports about EO, particularly with regard to how it may interact with specific genetic backgrounds. We [...] Read more.
The endogenous ouabain (EO) is a steroid hormone secreted by the adrenal gland with cardio-tonic effects. In this article, we have reviewed and summarized the most recent reports about EO, particularly with regard to how it may interact with specific genetic backgrounds. We have focused our attention on the EO’s potential pathogenic role in several diseases, including renal failure, essential hypertension and heart failure. Notably, these reports have demonstrated that EO acts as a pro-hypertrophic and growth-promoting hormone, which might lead to a cardiac remodeling affecting cardiovascular functions and structures. In addition, a possible role of EO in the development of acute kidney injury has been hypothesized. During the last decays, many important improvements permitted a deeper understanding of EO’s metabolisms and functions, including the characteristics of its receptor and the effects of its activation. Such progresses indicated that EO has significant implications in the pathogenesis of many common diseases. The patho-physiological role of EO in the development of hypertension and other cardiac and renal complications have laid the basis for the development of a new selective compound that could selectively modulate the genetic and molecular mechanisms involved in EO’s action. It is evident that the knowledge of EO has incredibly increased; however, many important areas remain to be further investigated. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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13 pages, 881 KiB  
Review
Genomics of Fibromuscular Dysplasia
by Silvia Di Monaco, Adrien Georges, Jean-Philippe Lengelé, Miikka Vikkula and Alexandre Persu
Int. J. Mol. Sci. 2018, 19(5), 1526; https://doi.org/10.3390/ijms19051526 - 21 May 2018
Cited by 30 | Viewed by 6447
Abstract
Fibromuscular Dysplasia (FMD) is “an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries” (Persu, et al; 2014). FMD can lead to hypertension, arterial dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia. The [...] Read more.
Fibromuscular Dysplasia (FMD) is “an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries” (Persu, et al; 2014). FMD can lead to hypertension, arterial dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia. The pathophysiology of the disease remains elusive. While familial cases are rare (<5%) in contemporary FMD registries, there is evidence in favour of the existence of multiple genetic factors involved in this vascular disease. Recent collaborative efforts allowed the identification of a first genetic locus associated with FMD. This intronic variant located in the phosphatase and actin regulator 1 gene (PHACTR1) may influence the transcription activity of the endothelin-1 gene (EDN1) located nearby on chromosome 6. Interestingly, the PHACTR1 locus has also been involved in vascular hypertrophy in normal subjects, carotid dissection, migraine and coronary artery disease. National and international registries of FMD patients, with deep and harmonised phenotypic and genetic characterisation, are expected to be instrumental to improve our understanding of the genetic basis and pathophysiology of this intriguing vascular disease. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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12 pages, 654 KiB  
Review
Kruppel-Like Factor 15 Is Critical for the Development of Left Ventricular Hypertrophy
by Sheila K. Patel, Jay Ramchand, Vincenzo Crocitti and Louise M. Burrell
Int. J. Mol. Sci. 2018, 19(5), 1303; https://doi.org/10.3390/ijms19051303 - 27 Apr 2018
Cited by 9 | Viewed by 4757
Abstract
Left ventricular hypertrophy (LVH) is an independent risk factor for adverse cardiovascular events and is often present in patients with hypertension. Treatment to reduce blood pressure and regress LVH is key to improving health outcomes, but currently available drugs have only modest cardioprotective [...] Read more.
Left ventricular hypertrophy (LVH) is an independent risk factor for adverse cardiovascular events and is often present in patients with hypertension. Treatment to reduce blood pressure and regress LVH is key to improving health outcomes, but currently available drugs have only modest cardioprotective effects. Improved understanding of the molecular mechanisms involved in the development of LVH may lead to new therapeutic targets in the future. There is now compelling evidence that the transcription factor Kruppel-like factor 15 (KLF15) is an important negative regulator of cardiac hypertrophy in both experimental models and in man. Studies have reported that loss or suppression of KLF15 contributes to LVH, through lack of inhibition of pro-hypertrophic transcription factors and stimulation of trophic and fibrotic signaling pathways. This review provides a summary of the experimental and human studies that have investigated the role of KLF15 in the development of cardiac hypertrophy. It also discusses our recent paper that described the contribution of genetic variants in KLF15 to the development of LVH and heart failure in high-risk patients. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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17 pages, 480 KiB  
Review
DNA Methylation and Histone Modification in Hypertension
by Shaunrick Stoll, Charles Wang and Hongyu Qiu
Int. J. Mol. Sci. 2018, 19(4), 1174; https://doi.org/10.3390/ijms19041174 - 12 Apr 2018
Cited by 74 | Viewed by 14893
Abstract
Systemic hypertension, which eventually results in heart failure, renal failure or stroke, is a common chronic human disorder that particularly affects elders. Although many signaling pathways involved in the development of hypertension have been reported over the past decades, which has led to [...] Read more.
Systemic hypertension, which eventually results in heart failure, renal failure or stroke, is a common chronic human disorder that particularly affects elders. Although many signaling pathways involved in the development of hypertension have been reported over the past decades, which has led to the implementation of a wide variety of anti-hypertensive therapies, one half of all hypertensive patients still do not have their blood pressure controlled. The frontier in understanding the molecular mechanisms underlying hypertension has now advanced to the level of epigenomics. Particularly, increasing evidence is emerging that DNA methylation and histone modifications play an important role in gene regulation and are involved in alteration of the phenotype and function of vascular cells in response to environmental stresses. This review seeks to highlight the recent advances in our knowledge of the epigenetic regulations and mechanisms of hypertension, focusing on the role of DNA methylation and histone modification in the vascular wall. A better understanding of the epigenomic regulation in the hypertensive vessel may lead to the identification of novel target molecules that, in turn, may lead to novel drug discoveries for the treatment of hypertension. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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15 pages, 18832 KiB  
Review
Comparative Genomics and Transcriptome Profiling in Primary Aldosteronism
by Elke Tatjana Aristizabal Prada, Isabella Castellano, Eva Sušnik, Yuhong Yang, Lucie S. Meyer, Martina Tetti, Felix Beuschlein, Martin Reincke and Tracy A. Williams
Int. J. Mol. Sci. 2018, 19(4), 1124; https://doi.org/10.3390/ijms19041124 - 09 Apr 2018
Cited by 11 | Viewed by 5651
Abstract
Primary aldosteronism is the most common form of endocrine hypertension with a prevalence of 6% in the general population with hypertension. The genetic basis of the four familial forms of primary aldosteronism (familial hyperaldosteronism FH types I–IV) and the majority of sporadic unilateral [...] Read more.
Primary aldosteronism is the most common form of endocrine hypertension with a prevalence of 6% in the general population with hypertension. The genetic basis of the four familial forms of primary aldosteronism (familial hyperaldosteronism FH types I–IV) and the majority of sporadic unilateral aldosterone-producing adenomas has now been resolved. Familial forms of hyperaldosteronism are, however, rare. The sporadic forms of the disease prevail and these are usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Aldosterone-producing adenomas frequently carry a causative somatic mutation in either of a number of genes with the KCNJ5 gene, encoding an inwardly rectifying potassium channel, a recurrent target harboring mutations at a prevalence of more than 40% worldwide. Other than genetic variations, gene expression profiling of aldosterone-producing adenomas has shed light on the genes and intracellular signalling pathways that may play a role in the pathogenesis and pathophysiology of these tumors. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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19 pages, 705 KiB  
Review
Non-Coding RNA in the Pathogenesis, Progression and Treatment of Hypertension
by Christiana Leimena and Hongyu Qiu
Int. J. Mol. Sci. 2018, 19(4), 927; https://doi.org/10.3390/ijms19040927 - 21 Mar 2018
Cited by 42 | Viewed by 5308
Abstract
Hypertension is a complex, multifactorial disease that involves the coexistence of multiple risk factors, environmental factors and physiological systems. The complexities extend to the treatment and management of hypertension, which are still the pursuit of many researchers. In the last two decades, various [...] Read more.
Hypertension is a complex, multifactorial disease that involves the coexistence of multiple risk factors, environmental factors and physiological systems. The complexities extend to the treatment and management of hypertension, which are still the pursuit of many researchers. In the last two decades, various genes have emerged as possible biomarkers and have become the target for investigations of specialized drug design based on its risk factors and the primary cause. Owing to the growing technology of microarrays and next-generation sequencing, the non-protein-coding RNAs (ncRNAs) have increasingly gained attention, and their status of redundancy has flipped to importance in normal cellular processes, as well as in disease progression. The ncRNA molecules make up a significant portion of the human genome, and their role in diseases continues to be uncovered. Specifically, the cellular role of these ncRNAs has played a part in the pathogenesis of hypertension and its progression to heart failure. This review explores the function of the ncRNAs, their types and biology, the current update of their association with hypertension pathology and the potential new therapeutic regime for hypertension. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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15 pages, 1142 KiB  
Review
Liddle Syndrome: Review of the Literature and Description of a New Case
by Martina Tetti, Silvia Monticone, Jacopo Burrello, Patrizia Matarazzo, Franco Veglio, Barbara Pasini, Xavier Jeunemaitre and Paolo Mulatero
Int. J. Mol. Sci. 2018, 19(3), 812; https://doi.org/10.3390/ijms19030812 - 11 Mar 2018
Cited by 65 | Viewed by 17113
Abstract
Liddle syndrome is an inherited form of low-renin hypertension, transmitted with an autosomal dominant pattern. The molecular basis of Liddle syndrome resides in germline mutations of the SCNN1A, SCNN1B and SCNN1G genes, encoding the α, β, and γ-subunits of the epithelial Na [...] Read more.
Liddle syndrome is an inherited form of low-renin hypertension, transmitted with an autosomal dominant pattern. The molecular basis of Liddle syndrome resides in germline mutations of the SCNN1A, SCNN1B and SCNN1G genes, encoding the α, β, and γ-subunits of the epithelial Na+ channel (ENaC), respectively. To date, 31 different causative mutations have been reported in 72 families from four continents. The majority of the substitutions cause an increased expression of the channel at the distal nephron apical membrane, with subsequent enhanced renal sodium reabsorption. The most common clinical presentation of the disease is early onset hypertension, hypokalemia, metabolic alkalosis, suppressed plasma renin activity and low plasma aldosterone. Consequently, treatment of Liddle syndrome is based on the administration of ENaC blockers, amiloride and triamterene. Herein, we discuss the genetic basis, clinical presentation, diagnosis and treatment of Liddle syndrome. Finally, we report a new case in an Italian family, caused by a SCNN1B p.Pro618Leu substitution. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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21 pages, 285 KiB  
Review
Advances in the Genetics of Hypertension: The Effect of Rare Variants
by Alessia Russo, Cornelia Di Gaetano, Giovanni Cugliari and Giuseppe Matullo
Int. J. Mol. Sci. 2018, 19(3), 688; https://doi.org/10.3390/ijms19030688 - 28 Feb 2018
Cited by 37 | Viewed by 8856
Abstract
Worldwide, hypertension still represents a serious health burden with nine million people dying as a consequence of hypertension-related complications. Essential hypertension is a complex trait supported by multifactorial genetic inheritance together with environmental factors. The heritability of blood pressure (BP) is estimated to [...] Read more.
Worldwide, hypertension still represents a serious health burden with nine million people dying as a consequence of hypertension-related complications. Essential hypertension is a complex trait supported by multifactorial genetic inheritance together with environmental factors. The heritability of blood pressure (BP) is estimated to be 30–50%. A great effort was made to find genetic variants affecting BP levels through Genome-Wide Association Studies (GWAS). This approach relies on the “common disease–common variant” hypothesis and led to the identification of multiple genetic variants which explain, in aggregate, only 2–3% of the genetic variance of hypertension. Part of the missing genetic information could be caused by variants too rare to be detected by GWAS. The use of exome chips and Next-Generation Sequencing facilitated the discovery of causative variants. Here, we report the advances in the detection of novel rare variants, genes, and/or pathways through the most promising approaches, and the recent statistical tests that have emerged to handle rare variants. We also discuss the need to further support rare novel variants with replication studies within larger consortia and with deeper functional studies to better understand how new genes might improve patient care and the stratification of the response to antihypertensive treatments. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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15 pages, 922 KiB  
Review
The Low-Renin Hypertension Phenotype: Genetics and the Role of the Mineralocorticoid Receptor
by Rene Baudrand and Anand Vaidya
Int. J. Mol. Sci. 2018, 19(2), 546; https://doi.org/10.3390/ijms19020546 - 11 Feb 2018
Cited by 36 | Viewed by 14417
Abstract
A substantial proportion of patients with hypertension have a low or suppressed renin. This phenotype of low-renin hypertension (LRH) may be the manifestation of inherited genetic syndromes, acquired somatic mutations, or environmental exposures. Activation of the mineralocorticoid receptor is a common final mechanism [...] Read more.
A substantial proportion of patients with hypertension have a low or suppressed renin. This phenotype of low-renin hypertension (LRH) may be the manifestation of inherited genetic syndromes, acquired somatic mutations, or environmental exposures. Activation of the mineralocorticoid receptor is a common final mechanism for the development of LRH. Classically, the individual causes of LRH have been considered to be rare diseases; however, recent advances suggest that there are milder and “non-classical” variants of many LRH-inducing conditions. In this regard, our understanding of the underlying genetics and mechanisms accounting for LRH, and therefore, potentially the pathogenesis of a large subset of essential hypertension, is evolving. This review will discuss the potential causes of LRH, with a focus on implicated genetic mechanisms, the expanding recognition of non-classical variants of conditions that induce LRH, and the role of the mineralocorticoid receptor in determining this phenotype. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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10 pages, 559 KiB  
Review
The T2238C Human Atrial Natriuretic Peptide Molecular Variant and the Risk of Cardiovascular Diseases
by Speranza Rubattu, Sebastiano Sciarretta, Simona Marchitti, Franca Bianchi, Maurizio Forte and Massimo Volpe
Int. J. Mol. Sci. 2018, 19(2), 540; https://doi.org/10.3390/ijms19020540 - 11 Feb 2018
Cited by 12 | Viewed by 3852
Abstract
Atrial natriuretic peptide (ANP) is a cardiac hormone which plays important functions to maintain cardio-renal homeostasis. The peptide structure is highly conserved among species. However, a few gene variants are known to fall within the human ANP gene. The variant rs5065 (T2238C) exerts [...] Read more.
Atrial natriuretic peptide (ANP) is a cardiac hormone which plays important functions to maintain cardio-renal homeostasis. The peptide structure is highly conserved among species. However, a few gene variants are known to fall within the human ANP gene. The variant rs5065 (T2238C) exerts the most substantial effects. The T to C transition at the 2238 position of the gene (13–23% allele frequency in the general population) leads to the production of a 30-, instead of 28-, amino-acid-long α-carboxy-terminal peptide. In vitro, CC2238/αANP increases the levels of reactive oxygen species and causes endothelial damage, vascular smooth muscle cells contraction, and increased platelet aggregation. These effects are achieved through the deregulated activation of type C natriuretic peptide receptor, the consequent inhibition of adenylate cyclase activity, and the activation of Giα proteins. In vivo, endothelial dysfunction and increased platelet aggregation are present in human subjects carrying the C2238/αANP allele variant. Several studies documented an increased risk of stroke and of myocardial infarction in C2238/αANP carriers. Recently, an incomplete response to antiplatelet therapy in ischemic heart disease patients carrying the C2238/αANP variant and undergoing percutaneous coronary revascularization has been reported. In summary, the overall evidence supports the concept that T2238C/ANP is a cardiovascular genetic risk factor that needs to be taken into account in daily clinical practice. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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