Erences including both blood pressure and heart rate in the response

Erences including both blood pressure and heart rate in the response to atenolol have been characterized FD&C Yellow 5 between Caucasians and African Americans, metabolic differences have not been previously associated with race. The racially disparate fatty acid signature induced by atenolol suggested genetic variation may also contribute to the differences observed between Caucasians and African Americans. We therefore tested the association between the top fatty acid signal oleic acid (Table 4) and SNPs on the 16 genes encoding lipases. In Caucasians but not African Americans, the LIPC SNP rs9652472 was associated with oleic acid change (p = 3.661024), whereas in African Americans but not Caucasians, the PLA2G4C SNP rs7250148 was associated with oleic acid change (p = 9.661025). Thus, the observed differences are explained at least in part by genetic differences that may yield different activities in lipases and corresponding differences in response to atenolol. These findings are consistent with our pharmacometabolomics results indicating that African Americans and Caucasians have distinct signatures in response to atenolol monotherapy. In summary, we showed that atenolol treatment causes a marked change in plasma fatty acid levels in Caucasians but not African Americans. We also showed that a SNP in the LIPC and PLA2G4C genes were associated with the change in oleic acid in Caucasians and African Americans, respectively. Specific racedependent changes in other metabolites such as the ketone body 3hydroxybutanoic acid and TCA cycle intermediate alpha ketoglutaric acid need to be further investigated. Pharmacometabolomics provides powerful tools to understand the mechanistic basis of variation in response to drug therapy. It complements information derived from pharmacogenomics and when combined, enables a systems pharmacology approach to increase our understanding of drug effects.AcknowledgmentsWe thank Andrew Lane for helpful comments on the manuscript.Author ContributionsConceived and designed the experiments: JAJ RFF RKD. Performed the experiments: HZ YG SB EC OF WRW. Contributed reagents/materials/ analysis tools: RCD ALB ABC JAJ. Wrote the paper: WRW RFF YG RKD.
Influenza continues to pose a global health problem, as highlighted by the 2009 swine influenza pandemic and sporadic human infections with avian H5N1 influenza viruses. Antigenic changes in influenza virus, primarily in the surface antigens hemagglutinin (HA) and neuraminidase (NA), are referred to as antigenic shift (subtype changes by reassortment) and antigenic drift (mutation). This variability among influenza viruses hinders vaccination efforts. Currently, PHCCC annual surveillance is necessary to identify circulating viral strains for use in vaccine production. New vaccines are often required, and take about 6 months to become available [1]. Thus new approaches are needed. In contrast, so-called “universal” vaccines targeting relatively conserved components of influenza virus can provide protection regardless of strain or subtype of virus, and may provide an alternative to the use of traditional vaccines. This immunity to conserved antigens would not necessarily prevent infection completely, but might decrease severity of disease, speed up viral clearance, and reduce morbidity and mortality during the initial stages of an outbreak until strain-matched vaccine becameavailable [2]. Furthermore, vaccines based on T cell immunity could be used in combination with a seasonal vaccine to.Erences including both blood pressure and heart rate in the response to atenolol have been characterized between Caucasians and African Americans, metabolic differences have not been previously associated with race. The racially disparate fatty acid signature induced by atenolol suggested genetic variation may also contribute to the differences observed between Caucasians and African Americans. We therefore tested the association between the top fatty acid signal oleic acid (Table 4) and SNPs on the 16 genes encoding lipases. In Caucasians but not African Americans, the LIPC SNP rs9652472 was associated with oleic acid change (p = 3.661024), whereas in African Americans but not Caucasians, the PLA2G4C SNP rs7250148 was associated with oleic acid change (p = 9.661025). Thus, the observed differences are explained at least in part by genetic differences that may yield different activities in lipases and corresponding differences in response to atenolol. These findings are consistent with our pharmacometabolomics results indicating that African Americans and Caucasians have distinct signatures in response to atenolol monotherapy. In summary, we showed that atenolol treatment causes a marked change in plasma fatty acid levels in Caucasians but not African Americans. We also showed that a SNP in the LIPC and PLA2G4C genes were associated with the change in oleic acid in Caucasians and African Americans, respectively. Specific racedependent changes in other metabolites such as the ketone body 3hydroxybutanoic acid and TCA cycle intermediate alpha ketoglutaric acid need to be further investigated. Pharmacometabolomics provides powerful tools to understand the mechanistic basis of variation in response to drug therapy. It complements information derived from pharmacogenomics and when combined, enables a systems pharmacology approach to increase our understanding of drug effects.AcknowledgmentsWe thank Andrew Lane for helpful comments on the manuscript.Author ContributionsConceived and designed the experiments: JAJ RFF RKD. Performed the experiments: HZ YG SB EC OF WRW. Contributed reagents/materials/ analysis tools: RCD ALB ABC JAJ. Wrote the paper: WRW RFF YG RKD.
Influenza continues to pose a global health problem, as highlighted by the 2009 swine influenza pandemic and sporadic human infections with avian H5N1 influenza viruses. Antigenic changes in influenza virus, primarily in the surface antigens hemagglutinin (HA) and neuraminidase (NA), are referred to as antigenic shift (subtype changes by reassortment) and antigenic drift (mutation). This variability among influenza viruses hinders vaccination efforts. Currently, annual surveillance is necessary to identify circulating viral strains for use in vaccine production. New vaccines are often required, and take about 6 months to become available [1]. Thus new approaches are needed. In contrast, so-called “universal” vaccines targeting relatively conserved components of influenza virus can provide protection regardless of strain or subtype of virus, and may provide an alternative to the use of traditional vaccines. This immunity to conserved antigens would not necessarily prevent infection completely, but might decrease severity of disease, speed up viral clearance, and reduce morbidity and mortality during the initial stages of an outbreak until strain-matched vaccine becameavailable [2]. Furthermore, vaccines based on T cell immunity could be used in combination with a seasonal vaccine to.