title: Pharmacometabolomics reveals racial differences in response to atenolol treatment.
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.
authors.affiliation: UC Davis Genome Center, University of California Davis, Davis, California, United States of America. wrwikoff@ucdavis.edu
authors.forename: William R
authors.initials: WR
authors.lastname: Wikoff
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.forename: Hongjie
authors.initials: H
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Stephen
authors.initials: S
authors.lastname: Boyle
authors.forename: Erik
authors.initials: E
authors.lastname: Churchill
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Rima
authors.initials: R
authors.lastname: Kaddurah-Daouk
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001262:Atenolol / Q000494:pharmacology / Q000627:therapeutic use; D016000:Cluster Analysis; D005260:Female; D023281:Genomics; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000208:ethnology* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D001262:Atenolol
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