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.
Highlights
Hypertension is the most common chronic disease world-wide with an estimated one billion individuals affected [1]
The aim of this study was to evaluate changes in the metabolome induced by treatment with atenolol and determine whether metabolomics provides novel mechanistic insight into racial differences in drug response
Our findings revealed a strong effect of atenolol on fatty acids that differed by race
Summary
Hypertension is the most common chronic disease world-wide with an estimated one billion individuals affected [1]. Metabolomics is a global biochemical approach that provides powerful tools for defining perturbations in metabolic pathways and networks in human disease [6,7,8,9,10]. Targeted and non-targeted metabolomic approaches have been used to define pathways implicated in variation of response to drugs such as escitalopram [11] and simvastatin [12,13] leading to the emergence of a new field: pharmacometabolomics [9,14,15]. Pharmacometabolomics can be used to define a unique signature that represents changes in the metabolome induced by drug treatment. This signature can provide insight into the mechanism of variation in drug response caused by factors including race and genetics
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