Cooper-Dehoff Rhonda M, Hou Wei, Weng Liming, Baillie Rebecca A, Beitelshees Amber L, Gong Yan, Shahin Mohamed H A, Turner Stephen T, Chapman Arlene, Gums John G, Boyle Stephen H, Zhu Hongjie, Wikoff William R, Boerwinkle Eric, Fiehn Oliver, Frye Reginald F, Kaddurah-Daouk Rima, Johnson Julie A
Department of Pharmacotherapy and Translational Research.
Circ Cardiovasc Genet. 2014 Apr;7(2):199-205. doi: 10.1161/CIRCGENETICS.113.000421. Epub 2014 Mar 13.
The 5-amino acid (AA) signature, including isoleucine, leucine, valine, tyrosine, and phenylalanine, has been associated with incident diabetes mellitus and insulin resistance. We investigated whether this same AA signature, single-nucleotide polymorphisms in genes in their catabolic pathway, was associated with development of impaired fasting glucose (IFG) after atenolol treatment.
Among 234 European American participants enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study and treated with atenolol for 9 weeks, we prospectively followed a nested cohort that had both metabolomics profiling and genotype data available for the development of IFG. We assessed the association between baseline circulating levels of isoleucine, leucine, valine, tyrosine, and phenylalanine, as well as single-nucleotide polymorphisms in branched-chain amino-acid transaminase 1 (BCAT1) and phenylalanine hydroxylase (PAH) with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the 5 AAs was associated with the following odds ratio and 95% confidence interval for IFG based on a fully adjusted model: isoleucine 2.29 (1.31-4.01), leucine 1.80 (1.10-2.96), valine 1.77 (1.07-2.92), tyrosine 2.13 (1.20-3.78), and phenylalanine 2.04 (1.16-3.59). The composite P value was 2×10(-5). Those with PAH (rs2245360) AA genotype had the highest incidence of IFG (P for trend=0.0003).
Our data provide important insight into the metabolic and genetic mechanisms underlying atenolol-associated adverse metabolic effects. Clinical Trial Registration- http://www.clinicaltrials.gov; Unique Identifier: NCT00246519.
包括异亮氨酸、亮氨酸、缬氨酸、酪氨酸和苯丙氨酸在内的5种氨基酸（AA）特征与新发糖尿病和胰岛素抵抗相关。我们研究了这种相同的AA特征，即其分解代谢途径中基因的单核苷酸多态性，是否与阿替洛尔治疗后空腹血糖受损（IFG）的发生有关。
在参加高血压反应药物基因组评估（PEAR）研究并用阿替洛尔治疗9周的234名欧美参与者中，我们前瞻性地跟踪了一个嵌套队列，该队列既有代谢组学分析数据，又有可用于IFG发生情况的基因型数据。我们评估了异亮氨酸、亮氨酸、缬氨酸、酪氨酸和苯丙氨酸的基线循环水平，以及支链氨基酸转氨酶1（BCAT1）和苯丙氨酸羟化酶（PAH）中的单核苷酸多态性与IFG发生情况之间的关联。所有基线AA水平均与IFG的发生密切相关。基于完全调整模型，5种氨基酸标准差的每一次增加与IFG的以下比值比和95%置信区间相关：异亮氨酸2.29（1.31 - 4.01），亮氨酸1.80（1.10 - 2.96），缬氨酸1.77（1.07 - 2.92），酪氨酸2.13（1.20 - 3.78），苯丙氨酸2.04（1.16 - 3.59）。综合P值为2×10⁻⁵。携带PAH（rs2245360）AA基因型的个体IFG发生率最高（趋势P值 = 0.0003）。
我们的数据为阿替洛尔相关不良代谢效应的代谢和遗传机制提供了重要见解。临床试验注册 - http://www.clinicaltrials.gov；唯一标识符：NCT00246519。
