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A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials

The Pharmacogenomics Journal volume 17, pages 192–200 (2017)Cite this article

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Abstract

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

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Acknowledgements

Julianna Keleti is a Clinical Trials Specialist at the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Simon de Denus holds the Université de Montréal Beaulieu-Saucier Chair in Pharmacogenomics.

Author contributions

Simon de Denus designed the substudy, interpreted the results and wrote the first draft of the manuscript; Marie-Pierre Dubé designed the substudy, analyzed the data and wrote the manuscript; Douglas L Mann, Gordon S Huggins, Thomas P Cappola, Svati Shah and Julianna Keleti designed the substudy and contributed to critical review and writing of the manuscript; Yassamin Feroz Zada, Sylvie Provost and Amina Bardhadi analyzed the data and wrote parts of the manuscript; Michael S Phillips, Valérie Normand and Ian Mongrain designed the custom panels and generated genetic data; Ian Mongrain wrote parts of the manuscripts; Michael S Phillips contributed to the design of the substudy; Valérie Normand contributed to critical review and writing of the manuscript.

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Authors and Affiliations

  1. Research Center, Montreal Heart Institute, Montreal, Quebec, Canada

    S de Denus, J L Rouleau & M-P Dubé

  2. Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada

    S de Denus, Y F Zada, S Provost, A Bardhadi, M S Phillips, V Normand, I Mongrain & M-P Dubé

  3. Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada

    S de Denus

  4. Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

    J L Rouleau & M-P Dubé

  5. Washington University School of Medicine, St Louis, MO, USA

    D L Mann

  6. Tufts Medical Center, Boston, MA, USA

    G S Huggins

  7. University of Pennsylvania, Philadelphia, PA, USA

    T P Cappola

  8. Division of Cardiology, Duke University School of Medicine, Durham, NC, USA

    S H Shah

  9. National Heart, Lung, and Blood Institute, Bethesda, MD, USA

    J Keleti

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Correspondence to S de Denus.

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Competing interests

Simon de Denus has received compensation from Servier for service as a consultant, was supported through grants from Pfizer, AstraZeneca, Roche and Novartis, and has received payment for lectures including service on speaker bureaus from Pfizer. Svati Shah holds a patent on an unrelated finding and has received grant support from Pfizer, Liposcience and Bristol-Meyers Squibb.

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de Denus, S., Rouleau, J., Mann, D. et al. A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials. Pharmacogenomics J 17, 192–200 (2017). https://doi.org/10.1038/tpj.2016.4

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