A functional variant of the NEDD4L gene is associated with beneficial treatment response with β-blockers and diuretics in hypertensive patients

Svensson-Färbom, Patrik; Wahlstrand, Björn; Almgren, Peter; Dahlberg, Jonas; Fava, Cristiano; Kjeldsen, Sverre E.; Hedner, Thomas; Melander, Olle

doi:10.1097/hjh.0b013e3283410390

Cited by 71 publications

(71 citation statements)

References 31 publications

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“…Variants of the NEDD4L gene may also contribute to individual variations in blood pressure 48) and to the outcome of treatment. For example, Svensson-Färbom, et al 49) showed that polymorphism in the NED-D4L gene (rs4149601) influences the efficacy of β-blockerand/or diuretic-based antihypertensive treatment but not diltiazem-based antihypertensive treatment. If the changes in the regulation of these two signaling components would be correlated with treatment efficacy in patients with heart failure (which requires further studies), they might become a genetic and genomic marker of kidney failure in AHF patients.…”

Section: Discussionmentioning

confidence: 99%

White Blood Cell Transcriptome Correlates With Renal Function in Acute Heart Failure

et al. 2012

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SummaryIt is notoriously difficult to classify patients with acute heart failure (AHF) because of variations in clinical presentation, different etiologies, the impact of comorbidities, and variable prognoses. In this study, we used DNA whole-genome microarrays to classify 24 patients with AHF based on the transcriptome of their peripheral blood nuclear cells. The main purpose was to verify whether any transcriptomic sub-clusters had clinical correlations. We identified two distinct groups of transcriptomic profiles that correlated with normal (1.125 mg/dL) and increased (1.783 mg/dL) mean blood creatinine concentrations. These two subgroups of patients (n = 12) differed in the expression of more than 6000 genes and 108 signaling pathways. The most significant regulated signaling pathway was the aldosterone-regulated sodium reabsorption pathway and the most significant regulated genes included the angiotensin-converting enzyme gene. This suggests that kidney impairment in patients with AHF is related to dysregulation of the renin-angiotensin-aldosterone system. The interesting findings of our study were the significant differences in expression of genes belonging to the aldosterone-regulated signaling pathway: Na + /K + transporting ATPase and NEDD4L (neuronal precursor cell expressed developmentally down-regulated 4-like) between patients with and without renal dysfunction. Future studies of bloodcell transcriptomic profiles in patients with AHF will provide further insights into the molecular pathogenesis of this cardiorenal disorder. (Int Heart J 2012; 53: 117-124)

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Section: Discussionmentioning

confidence: 99%

White Blood Cell Transcriptome Correlates With Renal Function in Acute Heart Failure

et al. 2012

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“…For example, in the Nordic Diltiazem Study (NORDIL), the G allele of rs4149601 was a predictor of thiazide and atenolol response over diltiazem response without consideration of other loci 72 . In contrast, it was the A allele of rs4149601 that was found to predict thiazide responsiveness in a case-control study of hypertensive Chinese subjects 73 .…”

Section: Candidate Variants Contributing To Sodium Reabsorptionmentioning

confidence: 99%

A Physiologic Approach to the Pharmacogenomics of Hypertension

Eadon

Chapman

2016

Advances in Chronic Kidney Disease

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“…The Nordic Diltiazem (NORDIL) study first showed that the blood pressure lowering effects of combination thiazide/β-blocker treatment were greater in carriers of the G allele compared to carriers of the AA genotype (reduction in systolic blood pressure [SBP] of 19.5 ± 16.8 mmHg versus 15.0 ± 19.3 mmHg; P <0.001 and reduction in diastolic blood pressure [DBP] of 15.4 ± 8.3 versus 14.1 ± 8.4 mmHg; P = 0.02 for carriers of the G allele and AA alleles, respectively). By contrast, no difference in response to the calcium channel blocker diltiazem was observed by NEDD4L genotype 39 . The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study then showed greater blood pressure lowering in patients with the G allele in response to hydrochlorothiazide but no difference by genotype in response to the β-blocker atenolol 40 .…”

Section: Hypertension Pharmacogenomicsmentioning

confidence: 73%

Hypertension pharmacogenomics: in search of personalized treatment approaches

Cooper‐DeHoff

Johnson

2015

Nat Rev Nephrol

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Cardiovascular and renal diseases are associated with many risk factors, of which hypertension is one of the most prevalent. Worldwide, blood pressure control is only achieved in ~50% of those treated for hypertension, despite the availability of a considerable number of antihypertensive drugs from different pharmacological classes. Although many reasons exist for poor blood pressure control, a likely contributor is the inability to predict to which antihypertensive drug an individual is most likely to respond. Hypertension pharmacogenomics and other ‘omics’ technologies have the potential to identify genetic signals that are predictive of response or adverse outcome to particular drugs, and guide selection of hypertension treatment for a given individual. Continued research in this field will enhance our understanding of how to maximally deploy the various antihypertensive drug classes to optimize blood pressure response at the individual level. This Review summarizes the available literature on the most convincing genetic signals associated with antihypertensive drug responses and adverse cardiovascular outcomes. Future research in this area will be facilitated by enhancing collaboration between research groups through consortia such as the International Consortium for Antihypertensives Pharmacogenomics Studies, with the goal of translating replicated findings into clinical implementation.

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A functional variant of the NEDD4L gene is associated with beneficial treatment response with β-blockers and diuretics in hypertensive patients

Cited by 71 publications

References 31 publications

White Blood Cell Transcriptome Correlates With Renal Function in Acute Heart Failure

White Blood Cell Transcriptome Correlates With Renal Function in Acute Heart Failure

A Physiologic Approach to the Pharmacogenomics of Hypertension

Hypertension pharmacogenomics: in search of personalized treatment approaches

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