Novel plasma biomarker of atenolol-induced hyperglycemia identified through a metabolomics-genomics integrative approach.
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.
de Oliveira, FA; Shahin, MH; Gong, Y; McDonough, CW; Beitelshees, AL; Gums, JG; Chapman, AB; Boerwinkle, E; Turner, ST; Frye, RF; Fiehn, O; Kaddurah-Daouk, R; Johnson, JA; Cooper-DeHoff, RM
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