Pharmacometabolomics Reveals Racial Differences in Response to Atenolol Treatment

• Type of Material: Article
• Authors: William R. Wikoff, University of California Davis; Reginald F. Frye, University of Florida; Hongjie Zhu, Duke University; Yan Gong, University of Florida; Stephen Boyle, Duke University; Erik Churchill, Duke University; Rhonda M. Cooper-Dehoff, University of Florida; Amber L. Beitelshees, University of Maryland; Arlene Chapman, Emory University; Oliver Fiehn, University of California Davis; Julie A. Johnson, University of Florida; Rima Kaddurah-Daouk, Duke University
• Language: English
• Date: 2013-03-11
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Wikoff et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0057639
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 8
• Issue: 3
• Start Page: e57639
• End Page: e57639
• Grant/Funding Information: The metabolomics work was funded by NIGMS (National Institute of General Medical Sciences) grant RC2-GM092729 “Metabolomics Network for Drug Response Phenotype”.; Additional support for this work includes: K23 grants HL091120 (ALB) and HL086558 (RCD); CTSA grants UL1-RR029890 (University of Florida), UL1-RR025008 (Emory University), and UL1-RR024150 (Mayo Clinic); and funds from the Mayo Foundation.; The PEAR study is supported by a grant from the National Institutes of Health (Bethesda, MD), grant # U01 GM074492, funded as part of the Pharmacogenetics Research Network.
• Keywords: GENE; THERAPY; MEN; WOMEN; HYPERTENSION; PHARMACOGENOMICS; Science & Technology; GLOBAL BIOCHEMICAL APPROACH; Multidisciplinary Sciences; Science & Technology - Other Topics; ETHNIC-DIFFERENCES; DRUG RESPONSE; METABOLOMICS; MULTIDISCIPLINARY SCIENCES
• Research Categories: Health Sciences, Pharmacology

Abstract

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.