NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo-DHF trial
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Published on: April 8, 2013
Leanne Dumeny1,2, Orly Vardeny3, Frank Edelmann4,5,6
1Center for Pharmacogenomics and Precision Medicine and Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Study Objective:
This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e'), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) participants.
Design:
Post-hoc genetic analysis.
Data Source:
Data and samples were derived from the multi-center, randomized, double-blind, placebo-controlled Aldo-DHF trial.
Patients:
Aldo-DHF participants treated with spironolactone (n = 184) or placebo (n = 178) were included.
Intervention:
Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing.
Measurements:
In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e' with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e'. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N-terminal peptide (PIIINP), and left atrial area.
Main Results:
Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e' over the 12-month course of the trial compared to noncarriers (β = 1.10; 95% confidence interval [CI]: 0.05-2.16; p = 0.04). No corresponding E/e' worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e'. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β = 0.83; 95% CI: 0.17-1.48; p = 0.01) and a greater reduction in diastolic blood pressure with spironolactone (β = -3.56; 95% CI: -6.73 to -0.39; p = 0.03). Serum PIIINP levels were similar across rs5522 genotypes.
Conclusions:
Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.
Insights
Spironolactone treatment may prevent worsening diastolic dysfunction in patients with the NR3C2 rs5522 G allele. Further studies are needed to confirm these findings in heart failure patients.
Area of Science:
- Cardiology
- Pharmacogenomics
- Genetics
Background:
- Diastolic heart failure (DHF) is a significant clinical challenge.
- Spironolactone, an aldosterone receptor antagonist, shows potential in treating DHF.
- Genetic variations may influence individual responses to spironolactone therapy.
Purpose of the Study:
- To investigate the association between genetic variants in NR3C2 and CYP11B2 and spironolactone response in DHF patients.
- To determine if specific genotypes affect diastolic function (E/e') and other cardiovascular markers.
Main Methods:
- Post-hoc genetic analysis of data from the Aldo-DHF trial.
- Genotyping of NR3C2 rs5522, NR3C2 rs2070951, and CYP11B2 rs1799998 in spironolactone and placebo groups.
- Multivariable linear regression to assess the association between genotypes and changes in E/e', blood pressure, and PIIINP.
Main Results:
- Carriers of the NR3C2 rs5522 G allele showed increased E/e' in the placebo group but not in the spironolactone group.
- The NR3C2 rs5522 G allele was associated with increased left atrial area in the placebo group.
- Spironolactone treatment in rs5522 G carriers led to a greater reduction in diastolic blood pressure.
Conclusions:
- Spironolactone may mitigate the progression of diastolic dysfunction linked to the NR3C2 rs5522 G allele.
- These findings suggest a pharmacogenetic interaction influencing spironolactone efficacy in DHF.
- Further validation studies are recommended to confirm these results.
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