Abstract
Introduction
While atenolol is an effective antihypertensive agent, its use is also associated with adverse events including hyperglycemia and incident diabetes that may offset the benefits of blood pressure lowering. By combining metabolomic and genomic data acquired from hypertensive individuals treated with atenolol, it may be possible to better understand the pathways that most impact the development of an adverse glycemic state.
Objective
To identify biomarkers that can help predict susceptibility to blood glucose excursions during exposure to atenolol.
Methods
Plasma samples acquired from 234 Caucasian participants treated with atenolol in the Pharmacogenomic Evaluation of Antihypertensive Responses trial were analyzed by gas chromatography Time-Of-Flight Mass Spectroscopy. Metabolomics and genomics data were integrated by first correlating participant’s metabolomic profiles to change in glucose after treatment with atenolol, and then incorporating genotype information from genes involved in metabolite pathways associated with glucose response.
Results
Our findings indicate that the baseline level of β-alanine was associated with glucose change after treatment with atenolol (Q = 0.007, β = 2.97 mg/dL). Analysis of genomic data revealed that carriers of the G allele for SNP rs2669429 in gene DPYS, which codes for dihydropyrimidinase, an enzyme involved in β-alanine formation, had significantly higher glucose levels after treatment with atenolol when compared with non-carriers (Q = 0.05, β = 2.76 mg/dL). This finding was replicated in participants who received atenolol as an add-on therapy (P = 0.04, β = 1.86 mg/dL).
Conclusion
These results suggest that β-alanine and rs2669429 may be predictors of atenolol-induced hyperglycemia in Caucasian individuals and further investigation is warranted.
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Acknowledgments
This study had financial support from the Pharmacogenomics Research Network (PGRN U01 GM074492), the Pharmacometabolomics Research Network (RC2-GM092729), and the National Center for Advancing Translational Sciences Clinical and Translational Science Award (NIH NCATS: UL1 TR000064, UL1TR000454, UL1 TR000135). PEAR efforts at the Mayo Clinic were also supported by funds from the Mayo Foundation.
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The research outlined in this manuscript stems from human subjects research. As indicated, the research protocol was approved by the Institutional Review Board at all of the enrolling sites, and all patients provided written, voluntary informed consent prior to participation in any research procedures.
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de Oliveira, F.A., Shahin, M.H., Gong, Y. et al. Novel plasma biomarker of atenolol-induced hyperglycemia identified through a metabolomics-genomics integrative approach. Metabolomics 12, 129 (2016). https://doi.org/10.1007/s11306-016-1076-8
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DOI: https://doi.org/10.1007/s11306-016-1076-8