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CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

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ABSTRACT

Purpose

This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure.

Methods

Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33).

Results

CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02–0.75] p = 0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84–10.30] p = 0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day).

Conclusion

Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

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Abbreviations

CLIA:

Clinical laboratory improvement amendments

CPMC:

Coriell personalized medicine collaborative

CYP2D6:

Cytochrome P450 family 2 subfamily D member 6

CYP2D6 :

Gene for cytochrome P450 family 2 subfamily D member 6

DPWG:

Dutch Pharmacogenetics Working Group

EM:

Extensive metabolizer

EMR:

Electronic medical record

IM:

Intermediate metabolizer

OSU:

Ohio State University

PharmGKB®:

Pharmacogenomics knowledgebase

PM:

Poor metabolizer

UM:

Ultra-rapid metabolizer

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ACKNOWLEDGMENTS AND DISCLOSURES

J.A.L. was supported by a Post-Doctoral Fellowship from the American Heart Association (14POST20100054) and the NIH student loan repayment program (L30 HL110279). P.F.B. is the James W. Overstreet Chair in Cardiology. J.P.K. was supported by a NIH Translational Scholar Career Advancement Award (K23 GM100372) and the NIH student loan repayment program (L32 MD006365). This work was also supported in part by NIH grant U01 GM92655 and a sub-award for the Translational Pharmacogenomics Project (TPP) via U01 HL105198 Pharmacogenomics of anti-platelet intervention-2 (PAPI-2) from NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Center for Advancing Translational Sciences. The Coriell Personalized Medicine Collaborative was funded by the William G. Rohrer Foundation, the RNR Foundation, and a grant from the endowment of the Coriell Institute for Medical Research.

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Authors and Affiliations

  1. Center for Pharmacogenomics, Ohio State University College of Medicine, Columbus, Ohio, USA

    Jasmine A. Luzum, Wolfgang Sadee & Joseph P. Kitzmiller

  2. Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church St., Ann Arbor, Michigan, 48109, USA

    Jasmine A. Luzum

  3. Division of Human Genetics, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, Ohio, USA

    Kevin M. Sweet

  4. Division of Cardiovascular Medicine and the Dorothy M. Davis Heart and Lung Research Institute, Ohio State University College of Medicine, Columbus, Ohio, USA

    Philip F. Binkley

  5. Coriell Institute for Medical Research, Camden, New Jersey, USA

    Tara J. Schmidlen, Joseph P. Jarvis & Michael F. Christman

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  1. Jasmine A. Luzum
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Luzum, J.A., Sweet, K.M., Binkley, P.F. et al. CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure. Pharm Res 34, 1615–1625 (2017). https://doi.org/10.1007/s11095-017-2104-8

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  • DOI: https://doi.org/10.1007/s11095-017-2104-8

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