Pharmacometabolomics reveals racial differences in response to atenolol treatment

William R Wikoff, Reginald F Frye, Hongjie Zhu, Yan Gong, Stephen Boyle, Erik Churchill, Rhonda M Cooper-Dehoff, Amber L Beitelshees, Arlene B Chapman, Oliver Fiehn, Julie A Johnson, Rima Kaddurah-Daouk, Pharmacometabolomics Research Network, William R Wikoff, Reginald F Frye, Hongjie Zhu, Yan Gong, Stephen Boyle, Erik Churchill, Rhonda M Cooper-Dehoff, Amber L Beitelshees, Arlene B Chapman, Oliver Fiehn, Julie A Johnson, Rima Kaddurah-Daouk, Pharmacometabolomics Research Network

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.

Conflict of interest statement

Competing Interests: YG serves on the editorial board for PLOS ONE. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Heat map showing the correlation…
Figure 1. Heat map showing the correlation of the change in a subset of metabolite concentrations with each other.
The fatty acids correlate with each other but not with threitol or alpha-ketoglutaric acid.
Figure 2. Metabolic network showing changes in…
Figure 2. Metabolic network showing changes in Caucasian subjects that occur as a result of atenolol treatment after 9 weeks.
Red color indicates that compounds decrease significantly in concentration; green indicates compounds that increase significantly in concentration. Bold blue lines indicate compounds related by a Kegg reaction pair, whereas others are related by structural similarity.
Figure 3. Alternative model of a potential…
Figure 3. Alternative model of a potential mechanism for atenolol treatment on plasma free fatty acid concentrations.

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