de Oliveira Felipe A, Shahin Mohamed H, Gong Yan, McDonough Caitrin W, Beitelshees Amber L, Gums John G, Chapman Arlene B, Boerwinkle Eric, Turner Stephen T, Frye Reginald F, Fiehn Oliver, Kaddurah-Daouk Rima, Johnson Julie A, Cooper-DeHoff Rhonda M
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610-0486, USA.
Department of Medicine, University of Maryland, Baltimore, MD, USA.
Metabolomics. 2016 Aug;12(8). doi: 10.1007/s11306-016-1076-8. Epub 2016 Jul 13.
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.
To identify biomarkers that can help predict susceptibility to blood glucose excursions during exposure to atenolol.
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.
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 , 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).
These results suggest that β-alanine and rs2669429 may be predictors of atenolol-induced hyperglycemia in Caucasian individuals and further investigation is warranted.
虽然阿替洛尔是一种有效的抗高血压药物，但其使用也与不良事件相关，包括高血糖和新发糖尿病，这些可能会抵消降压带来的益处。通过整合从接受阿替洛尔治疗的高血压个体中获取的代谢组学和基因组数据，有可能更好地了解对不良血糖状态发展影响最大的途径。
识别有助于预测阿替洛尔治疗期间血糖波动易感性的生物标志物。
在抗高血压反应的药物基因组学评估试验中，对234名接受阿替洛尔治疗的白种人参与者采集的血浆样本进行气相色谱飞行时间质谱分析。代谢组学和基因组学数据的整合方法是，首先将参与者的代谢组学谱与阿替洛尔治疗后的血糖变化相关联，然后纳入与葡萄糖反应相关的代谢途径中涉及的基因的基因型信息。
我们的研究结果表明，β-丙氨酸的基线水平与阿替洛尔治疗后的血糖变化相关（Q = 0.007，β = 2.97mg/dL）。基因组数据分析显示，基因中SNP rs2669429的G等位基因携带者，该基因编码二氢嘧啶酶（一种参与β-丙氨酸形成的酶），与非携带者相比，在接受阿替洛尔治疗后血糖水平显著更高（Q = 0.05，β = 2.76mg/dL）。这一发现在接受阿替洛尔作为附加治疗的参与者中得到了重复验证（P = 0.04，β = 1.86mg/dL）。
这些结果表明，β-丙氨酸和rs2669429可能是白种人个体中阿替洛尔诱导的高血糖的预测指标，值得进一步研究。
