Is Diabetes Mellitus-Linked Amino Acid Signature Associated With β-Blocker-Induced Impaired Fasting Glucose?
Is Diabetes Mellitus-Linked Amino Acid Signature Associated With β-Blocker-Induced Impaired Fasting Glucose?
复制标题
DOI：
10.1161/circgenetics.113.000421
复制
发表时间：
2014-04-01
影响因子：
--
通讯作者：
Johnson, Julie A.
中科院分区：
文献类型：
--
作者：
Cooper-DeHoff, Rhonda M.;Hou, Wei;Johnson, Julie A.
背景-5-氨基酸（AA）信号，包括异亮氨酸、亮氨酸、缬氨酸、酪氨酸和苯丙氨酸，与糖尿病和胰岛素抵抗有关。我们研究了是否相同的AA签名，单核苷酸多态性的基因在他们的分解代谢途径，与发展受损空腹血糖（IFG）后阿替洛尔treatment.Methods和Results-Among 234欧洲美国参与者参加了药物基因组学评价抗高血压反应（PEAR）研究和治疗阿替洛尔9周，我们前瞻性地跟踪了一个嵌套队列，该队列具有代谢组学分析和基因型数据，可用于IFG的发展。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（BCAT 1）和苯丙氨酸羟化酶（PAH）的单核苷酸多态性与IFG发生之间的关系。所有基线AA水平与IFG的发展密切相关。基于完全校正的模型，5个AA的标准差的每个增量与以下IFG的比值比和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）和苯丙氨酸2.04（1.16-3.59）。复合P值为2 × 10 ~（-5）。PAH（rs 2245360）AA基因型者IFG的发生率最高（趋势P =0.0003）。结论-我们的数据为深入了解阿替洛尔相关不良代谢作用的代谢和遗传机制提供了重要依据。临床试验注册-http：www.clinicaltrials.gov;唯一标识符：NCT 00246519
Background-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.Methods and Results-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 2x10(-5). Those with PAH (rs2245360) AA genotype had the highest incidence of IFG (P for trend=0.0003).Conclusions-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