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The genetics of loop diuretic effects

The Pharmacogenomics Journal volume 12, pages 45–53 (2012)Cite this article

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Abstract

Little is known about the genetic impact on loop diuretic effects. We newly investigated five genetic polymorphisms in 95 healthy volunteers, who had ingested bumetanide, frusemide and torsemide. The subjects excreted means of 20.2 g sodium chloride, 2.87 g potassium and 261 mg calcium over 24 h. Concerning sodium chloride, the subjects excreted 2.2 g less per two T-alleles of C825T in the G nucleotide β-subunit 3 (GNB3), 3.2 g less per two Met32-alleles of Val32Met in the atrial natriuretic peptide precursor (ANP) and 2.8 g more per two Arg152-alleles of Ter152Arg in ANP (P=0.007, 0.05 and 0.007). Concerning potassium, the subjects excreted 0.42 g more per two ANP Arg152-alleles (P=0.023). Concerning calcium, the subjects excreted 32 mg more per two deletion-alleles of the insertion/deletion polymorphism in the angiotensin-converting enzyme, 44 mg more per two Trp460-alleles of Gly460Trp in α-adducin (ADD1) and 42 mg less per two GNB3 T-alleles (P=0.006, 0.023 and 0.008). The common genetic impact together with three polymorphisms in the sodium chloride cotransporter and the epithelial sodium channel was 20, 15, 10 and 23% of the variation in the urinary excretion of sodium chloride, volume, potassium and calcium. This exceeded the fraction of variation explained by differences in the pharmacokinetics: 13, 10, 11 and 6%. Thus, genetic variation seems to be a stronger predictor of the loop diuretic drug response than pharmacokinetic variation.

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Acknowledgements

The study was supported in part by the German national genome research network (NGFN) grants 01GS0107, 01GS0157, 01GR0462 and 01GR0416. The skillful contributions of Alexandra Zirk, Michaela Torn, Franziska Tuchen and Jan Westermann to the clinical study and those of Sabine Engelhardt, Ellen Bruns and Ines Müller to the drug concentration analyses are gratefully acknowledged.

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  1. Department of Clinical Pharmacology, University Medical Center, Georg-August-University, Göttingen, Germany

    S V Vormfelde & J Brockmöller

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  1. S V Vormfelde
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Correspondence to S V Vormfelde.

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Vormfelde, S., Brockmöller, J. The genetics of loop diuretic effects. Pharmacogenomics J 12, 45–53 (2012). https://doi.org/10.1038/tpj.2010.68

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