A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals

Brugts, Jasper J.; Isaacs, Aaron; Maat, Moniek P.M. de; Boersma, Eric; Duijn, C.M. van; Akkerhuis, K. Martijn; Uitterlinden, André G.; Witteman, Jacqueline C. M.; Cambien, François; Ceconi, Claudio; Remme, Willem J.; Bertrand, Michel E.; Ninomiya, Toshiharu; Harrap, Stephen B; Chalmers, John; MacMahon, Stephen; Fox, Kim; Ferrari, Roberto; Simoons, Maarten L.; Danser, A.H. Jan

doi:10.1097/hjh.0b013e328341d117

Cited by 48 publications

(27 citation statements)

References 37 publications

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“…This does not necessarily mean that HCM patients will not benefit from the prescription of drugs blocking the RAAS system. 35 However, small studies showing a positive effect of RAAS inhibitors on progression of hypertrophy and fibrosis in HCM need confirmation. 36,37 Furthermore, our study was limited to five candidate polymorphisms and the role of other common genetic variants in explaining phenotypic variability among HCM patients, which may act in a mutation-specific way, merits investigation perhaps in future genome-wide association studies.…”

Section: Discussionmentioning

confidence: 99%

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

et al. 2012

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The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P ¼ 0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.

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Section: Discussionmentioning

confidence: 99%

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

et al. 2012

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“…Genetic variation has been evaluated, usually by studying single nucleotide polymorphisms in RAAS genes in a retrospective manner in large clinical trials. 53,54 Emphasis has been on the ACE insertion/ deletion polymorphism. 55 Unfortunately, the effects were small and difficult to replicate, and, given the nonexistence of large prospective studies to further evaluate these findings, at this stage, there is no useful genetic information that can be applied to the individual patient to help choosing a specific RAAS blocker.…”

Section: Determinants Of Raas Blocker Response and The Degree Of Blocmentioning

confidence: 99%

Hypertension

Riet

Esch

Roks

et al. 2015

Circulation Research

545

251

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Blockers of the renin–angiotensin–aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension.

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“…Similar studies reported association of RAAS polymorphisms with response to ACEinhibitor therapy. 20,21 To our knowledge this is the first paper that describes the association between AGTR1 gene polymorphisms and hypertension in the Mexican population. The AGTR1 +573 C/T (rs5182) polymorphism was associated with the risk of developing hypertension in this population.…”

Section: Discussionmentioning

confidence: 99%

Association of angiotensin II type 1-receptor gene polymorphisms with the risk of developing hypertension in Mexican individuals

Martínez‐Rodríguez

Posadas‐Romero

Cardoso

et al. 2011

J Renin Angiotensin Aldosterone Syst

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Introduction: Hypertension is a complex disease in which a significant interaction between genetic and environmental factors takes place. The renin-angiotensin system plays an important role regulating blood pressure to maintain homeostasis and vascular tone. In the present work, the role of angiotensin II type 1-receptor (AGTR1) gene polymorphisms as susceptibility markers for hypertension was evaluated. Materials and methods: Five polymorphisms in the AGTR1 gene were genotyped by 5′ exonuclease TaqMan genotyping assays in 239 hypertensive and 371 non-hypertensive individuals. Results: A similar distribution of rs275651, rs275652, rs275653, and rs5183 polymorphisms was observed in both studied groups. Different distribution of rs5182 genotypes was observed between the studied groups (p = 0.016). According to the co-dominant model, individuals with rs5182 CC genotype have a 1.83-fold increased risk of developing hypertension (p = 0.009). Polymorphisms were distributed in two blocks: block 1 included the rs275651, rs275652, and rs275653 polymorphisms, whereas block 2 included the rs5183 and rs5182 polymorphisms. Individuals with hypertension showed increased frequency of 'CA' haplotype of block 2 when compared to non-hypertensive individuals (p = 0.015, odds ratio = 1.33). Conclusion:The results suggest that the rs5182 gene polymorphism could be involved in the risk of developing hypertension in Mexican individuals.

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A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals

Abstract: This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals.

Cited by 48 publications

References 37 publications

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

Hypertension

Association of angiotensin II type 1-receptor gene polymorphisms with the risk of developing hypertension in Mexican individuals

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