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Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide

The Pharmacogenomics Journal volume 15, pages 153–157 (2015)Cite this article

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Abstract

Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.

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Acknowledgements

We acknowledge and thank the valuable contributions of the study participants, study physicians, support staff and the technical assistance: Zhiying Wang, Megan Grove, Jodie Van De Rostyne, Jeremy Palbicki, Robert Tarrell and Prabin Thapa. GERA was supported by NIH Grants HL74735 and HL53335, and the Mayo Foundation. PEAR was supported by an NIH Grant U01 GM074492, funded as part of the Pharmacogenomics Research Network. This work is also supported by the following grants from the NIH National Center for Research Resources: Grants M01 RR00082 and UL1 RR029890 to the University of Florida, Grants UL1 RR025008 and M01 RR00039 to Emory University and Grant UL1 RR024150 to Mayo Clinic.

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Authors and Affiliations

  1. Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA

    J L Del-Aguila & E Boerwinkle

  2. Department of Pharmacotherapy and Translational Research and Division of Cardiovascular Medicine and Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA

    R M Cooper-DeHoff, J G Gums & J A Johnson

  3. Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

    A B Chapman

  4. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    A L Beitelshees

  5. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    K Bailey & S T Turner

  6. Human Genome Sequencing Center at Baylor College of Medicine, Houston, TX, USA

    E Boerwinkle

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  1. J L Del-Aguila
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Correspondence to E Boerwinkle.

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Supplementary Information accompanies the paper on the Journal of Exposure Science and Environmental Epidemiology website

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Del-Aguila, J., Cooper-DeHoff, R., Chapman, A. et al. Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide. Pharmacogenomics J 15, 153–157 (2015). https://doi.org/10.1038/tpj.2014.46

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